Johansson et al.; The NLRC4 inflammasome and IL-18 in ...

DOI: 10.1161/CIRCGENETICS.114.000724

1

The NLRC4 Inflammasome Is an Important Regulator of Interleukin-18Levels in Patients with Acute Coronary Syndromes: A Genome-Wide

Association Study in the PLATO Trial

Running title: Johansson et al.; The NLRC4 inflammasome and IL-18 in ACS patients

Åsa Johansson, PhD1,2; Niclas Eriksson, PhD1; Richard C. Becker, MD3; Robert F. Storey, MD,

DM4; Anders Himmelmann, MD, PhD5; Emil Hagström, MD, PhD1,6,7; Christoph Varenhorst,

MD, PhD1,6; Tomas Axelsson, PhD8; Bryan J. Barratt, PhD9; Stefan K. James, MD, PhD1,6;

Hugo A. Katus, MD, PhD10; Gabriel Steg, MD11-14; Ann-Christine Syvänen, PhD8; Lars

Wallentin, MD, PhD1,6; Agneta Siegbahn, MD, PhD1,15 on behalf of the PLATO Investigators

1Uppsala Clinical Research Ctr, 2Dept of Immunology, Genetics & Pathology, 6Dept of Medical Sciences, Cardiology, 8Dept of Medical Sciences, Molecular Medicine, Science for Life Laboratory, 15Dept of Medical

Sciences, Clinical Chemistry, Uppsala Univ, Uppsala, Sweden; 3Division of Cardiovascular Health & Disease, Heart, Lung & Vascular Institute, Academic Health Ctr, Cincinnati, OH; 4Dept of Cardiovascular Science, Univ of

Sheffield, Sheffield, UK; 5AstraZeneca Research & Development, Mölndal, Sweden; 7Duke Clinical Research Institute, Duke Univ Medical Ctr, Durham, NC; 9AstraZeneca R&D, Alderley Park, Cheshire, UK; 10Medizinishe Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany; 11INSERM-Unité 1148; 12Assistance Publique-

Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat; 13Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France; 14NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK

Correspondence:

Åsa Johansson, PhD Agneta Siegbahn, MD, PhD

Dept of Immunology, Genetics & Pathology Dept of Medical Sciences, Clin Chem

BMC, Husargatan 3, Box 815 Uppsala University, University Hospital

SE-751 08 Uppsala, Sweden 751 85 Uppsala, Sweden

Tel: +46 702 51 31 32 Tel: +46 704 250666

Fax: +46 18 51 55 17 Fax: +46-18-552562

E-mail: [email protected] E-mail: [email protected]

Journal Subject Codes: [108] Other myocardial biology, [89] Genetics of cardiovascular disease

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2

Abstract:

Background - Interleukin 18 (IL-18) promotes atherosclerotic plaque formation and is increased

in patients with acute coronary syndromes (ACS). However the relative contribution of genetic

variants to the IL-18 levels has not been fully evaluated.

Methods and Results - Baseline plasma IL-18 levels were measured in 16633 ACS patients, of

whom 9340 had genetic data that passed genotype quality control. A two-stage genome-wide

association study (GWAS) was performed, followed by combined analyses using over 10 million

genotyped or imputed genetic markers. SNPs at three loci (IL18, NLRC4, and MROH6), were

identified (P < 3.15 × 10 8) in the discovery cohort (N=3777) and replicated in the remaining

patients (N=5563). In the pooled data (discovery + replication cohort), seven independent

associations, in five chromosomal regions, were associated with IL-18 levels (minimum P = 6.99

× 10-72). Six SNPs are located in predicted promoter regions of which one disrupts a transcription

factor binding site. One SNP in NLRC4 is a rare missense variant, predicted to be deleterious to

the protein. Altogether, the identified genetic variants explained 8% of the total variation in IL-

18 levels in the cohort.

Conclusions - Our results show that genetic variants play an important role in determining IL-18

levels in patients with ACS and we have identified genetic variants located in the IL-18 gene

(IL18) or close to genes that are involved in procaspase-1 activation (NLRC4, and CARD16,

CARD17, and CARD18. These associations also highlight the importance of the NLRC4

inflammasome for IL-18 production in ACS patients.

Key words: genome wide association study, acute coronary syndrome, interleukin

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3

Introduction

Acute coronary syndromes (ACS) are a major cause of emergency hospital care and have a high

morbidity and mortality. A large number of biomarkers have been investigated in patients with

ACS and found to be related to worse disease outcomes. Interleukin-18 (IL-18), a member of the

IL-1 cytokine superfamily, is an interferon (IFN) -inducing factor 1 and is expressed in

atherosclerotic plaques 2. IL-18 has been associated with destabilization of plaques leading to

subsequent thrombotic events 3. It is known that IL-18 is increased in patients with acute

myocardial infarction (MI) 4 and an association between baseline levels of IL-18 and recurrent

cardiovascular events has been reported 5, 6.

Experiments in mice have shown that IL-18 promotes atherosclerosis through the release

7, highlighting the inflammatory context of atherosclerosis. Similarly, expression

plasmid DNA encoding murine IL-18-binding protein (BP) has been associated with reduced

atherosclerotic plaque progression, resulting in more stable plaques 8. This is consistent with the

expression of IL-18 being higher in unstable compared to stable plaques in humans 2. Despite the

wide range of data relating IL-18 to clinical and subclinical cardiovascular disease, no prior

large-scale genetic study of IL-18 has been performed in patients with ACS.

In order to gain a better understanding of the molecular mechanisms behind IL-18 release

in ACS, we aimed to identify genetic variants that influence IL-18 levels. A genome-wide

association study (GWAS) for IL-18 was performed in a large contemporary cohort of all types

of ACS. Our results show that genetic variants play an important role in IL-18 variation and

highlight the importance of the NLRC4 inflammasome for IL-18 production in patients with

ACS.

ls of IL-18 and recucucucurr

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NA encoding murine IL-18-binding protein (BP) has been associated with reduce

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of IL 18 being higher in nstable compared to stable plaq es in h mans 2 Desp

perimemementnttntsss inininn mmicicicice have shown that IL-1888 ppprromotes atheroscsclelll rosis through the re

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4

Methods

Study Cohort

The PLATelet inhibition and patient Outcomes (PLATO) trial (Clinical Trial Registration:

www.clinicaltrials.gov; NCT00391872) was a prospective randomized clinical trial that

compared the effect of ticagrelor versus clopidogrel in 18,624 patients with ACS. The design,

population, baseline clinical characteristics and primary results of the PLATO trial have

previously been published 9, 10. The trial was performed in accordance with the Declaration of

Helsinki and approved by regulatory authorities in all participating countries and by participating

sites’ institutional review boards. All participants provided written informed consent.

Participation in the genetic substudy was voluntary and required an additional consent form at

the time of enrollment in the genetic sub study.

Biomarker Laboratory Analysis

Baseline venous blood samples for biomarker investigations were collected, for all patients, in

EDTA tubes within 24 hours of admission, prior to the administration of study medication.

During the index hospitalization, an additional venous blood sample was collected in EDTA

tubes for genetic analyses for 10,013 individuals. Additional samples, in a serial sample sub

cohort, were taken at a second visit at the hospital, approximately one month (mean 31.3,

standard deviation 8.0 days) after randomization. Venous blood samples were centrifuged and

plasma samples were frozen at -70°C until analyzed centrally at the Uppsala Clinical Research

Centre (UCR) laboratory, Uppsala, Sweden. IL-18 levels were measured at baseline and at the

second visit using MBL human IL-18 ELISA (Naka-ku, Nagoya, Japan), with a total precision of

9%.

untries and by partrtrtticicicici

ormed ddd consent.ttt

on in the genetic substudy was voluntary and required an additional consent form

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e s

es ithin 24 ho rs of admission prior to the administration of st d medication

on ininnn ttthehehehe ggenenenettticicicic substudy was voluntary yy anaand required an adadaddiddd tional consent form

eene rrror llment in thhhe gegeenetitiiticc c subbbb studuudy.

r Laboboboborarararatttory AAAAnalllysis s

enous blood samppplell s ffof r bibb omarkkkek r investigigi atiioi ns were collllllected,dd,d for all papp tients

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5

Genotyping

A two-stage design was used for the genome-wide association study (GWAS), with a discovery

cohort and a replication cohort, followed by combined analyses of the pooled discovery and

replication cohort. The discovery cohort consisted of a random set of 3,998 patients genotyped

using the Illumina HumanOmni2.5-4v1 (Omni2.5) BeadChip (Illumina, San Diego, CA), and the

replication cohort of the remaining 6,015 patients, which were genotyped using the Illumina

Infinium HumanOmniExpressExome-8v1 BeadChip (Illumina, San Diego, CA). Genotyping was

performed according to the manufacturer's instructions. Analysis of the raw data was performed

using Illumina GenomeStudio 2011.1 (Illumina, San Diego, CA), the Illumina´s Infinium assay

and project sample generated cluster files 11, 12. Quality controls (QC) were performed using the

whole genome association analysis toolset PLINK v1.07 13

(http://pngu.mgh.harvard.edu/purcell/plink) in the discovery and replication cohorts separately

(Supplemental Material Table S1).

Imputations of ungenotyped SNPs

Imputations were performed in the discovery and replication cohorts separately (Supplemental

Material Table S1) using a pre-phasing approach 14 implemented in SHAPEIT version 2 15 and

IMPUTE2 (version 2.2.2) 16. The 1000 Genomes 17 Phase I integrated variant set (NCBI build

b37, Mar 2012, updated 24 Aug 2012) were accessed from the IMPUTE2 web site and used as

reference panel. Post-imputation QC was performed using QCTOOL version 1.3

(http://www.well.ox.ac.uk/~gav/qctool). Imputed data from the discovery and replication cohorts

were merged based on the SNP position (Supplemental Material Table S1).

Statistical analyses

Pair-wise kinship matrices were calculated for the replication and discovery cohorts separately

e raw data was perererrfofofof r

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omememee association anaalylylylysiissss ttot ollllsseset PLLINNNKK vv1.07 77 1131

u.mghhh.hahahaharrrvarrd.dd ddededu/u//pupurcr ellll/l/l/pppplilililink) ))) ininin ththhhe dididdiscscovovoverrerery ananand dd reerere lplplicici ttatation nnn cococohhhhortrttss sesepaparar t

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6

and together, using genotyped autosomal single nucleotide polymorphisms (SNPs [Supplemental

Material Table S1]) and the ibs function (weighted by the allele frequency), which is

implemented in GenABEL 18. The kinship matrix was used to calculate the pair-wise distance

matrix between individuals followed by classical multidimensional scaling (MDS) analyses

using 10 dimensions.

A large set of clinical variables were tested prior to association analyses (Supplemental

Material Table S2). The selection of covariables for the genetic analyses was performed in two

steps. Firstly, each variable was tested in the discovery cohort using a simple linear regression

model with log transformed IL-18 as dependent variable. Secondly, all variables that were

significantly explanatory for IL-18 at the significance level of P < 0.1 were included in a

multiple linear regression model (Supplemental Material Table S3). Only variables with P < 0.1

in the multiple linear regression model were included as covariables in the genome-wide

association analyses.

In the GWAS, IL-18 was analyzed on log scale (to avoid a heavy-tailed variable) using a

linear regression model implemented as the mlreg function in the GenABEL R library18. To

adjust for possible population stratification, all genome-wide association analyses were adjusted

for the four first genetic principal components 19. GWAS analyses were initially performed in the

discovery cohort, using genotyped SNPs only. To adjust for the number of statistical tests

performed, a genome-wide significance level, according to the Bonferroni method, was set at P =

3.152 × 10 8 (0.05/1,586,429 SNPs). All SNPs that passed the threshold for significance were

taken forward for replication, using the same set of covariates. Since the discovery and

replication cohorts were not genotyped using the same array, we used imputed genotypes for the

replication where necessary. Imputed SNP data were analyzed using the palinear function in the

simple linear reggrerereresssss

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he GWAS IL 18 as anal ed on log scale (to a oid a hea tailed ariable) s

y exexexplplplp anananatatatoroo y y fofofofor IL-18 at the significannnccce level of P < 0.111 wwwere included in a P

neeae rrr r regressionn mmmodddeeele ((SuSuSuS pplelelel meeenntalll MMatterrialll TTTabababllel SSS33). OnOnOnlyyy vvvariaaaablblblblesss wwwithhh h P P

iple lillilineneneneararara reggreressssioioi nn mom dededellll were iiincncncnclululul dededd ddd aas cccoooovararariiiiablblbleseeses iiinn ththththe gegegegennnomeme- iwiwiidededd

analysyy es.

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7

ProbABEL package 20. The threshold for significance for a successful replication was set to P =

0.05/number of SNPs to be replicated.

Finally, the pooled imputed data from the discovery and replication cohorts were

analyzed together. To test for independent genetic effects in the pooled sample, the most

significant SNP from the primary analyses was added to the previously used covariables and a

new round of GWAS analyses were performed. This process, adding the most significant SNP

from the previous round to the covariables and rerunning the analyses, was repeated until no

genome-wide significant SNP was detected. In the pooled analyses, we used the same threshold

for significance as in the discovery GWAS (P < 3.152 × 10 8). To compare IL-18 levels at

baseline and at the second visit (approximately 1 month later), we tested if the difference

between visits two and baseline deviated from zero, using Wilcoxon rank test.

Bioinformatic analyses

The top SNPs from each independent genetic association signal were imported as custom tracks

into the UCSC genome browser (Human Feb. 2009 GRCh37/hg19 Assembly, Data retrieved

April 26th, 2013). The location of the associated SNPs were compared to the location of 1)

Known human protein-coding and non-protein-coding genes taken from the National Center for

Biotechnology Information (NCBI) RNA reference sequences collection (RefSeq genes – last

updated 2012-04-25), 2) Regions where transcription factors bind to DNA as assayed by ChIP-

seq (Transcription Factor ChIP-seq from ENCODE (USF-1) - Last Updated: 2012-05-25), and

3) Chromatin state segmentation for nine human cell types 21, 22 using the ENCODE Mar 2012

Freeze. SIFT (Sorting Intolerant From Tolerant) 23 and PolyPhen (Polymorphism Phenotyping) 24

scores were retrieved from Ensembl database (http://www.ensembl.org, accessed – 28, August

2013).

e used the same thrhrhrhreseee

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8

Results

Clinical variables

The clinical background and baseline characteristics were similar in the discovery (N=3998) and

replication (N=6015) cohorts (Supplemental Material Table S4 and Table S5). A large number of

clinical variables are likely to influence IL-18 levels, and including those as covariates (precision

variables) in the analyses might increase our power to detect association between SNPs and IL-

18. We identified seven variables (age, sex, body mass index [BMI], medical history of diabetes

mellitus, peripheral artery disease and chronic renal disease, and lipid-lowering agent at day of

randomization) to be included as covariates in the association analyses (Figure 1, Supplemental

Material Table S3). The study includes individuals with different genetic origins (Supplemental

Material Figure S1). Therefore, we also included the first four principal components

(Supplemental Material Figure S1) as covariates (confounders) in the association analyses, since

they might affect both IL-18 levels and SNPs by differences in allele frequencies and IL-18

levels between population groups (Figure 1).

GWAS

A total of 3982 and 5996 patients passed genotype QC of which 3777 and 5563 had IL-18

measurements available in the discovery and replication cohort respectively. In the primary

GWAS in the discovery cohort, a total of 110 genome-wide significant SNPs (Supplemental

Material Table S6), located in three chromosomal regions, were identified. The largest region on

chromosome 2 included 100 significant SNPs (minimum P = 6.31 × 10-31) located within or

close to NLRC4. The second largest region on chromosome 11 consisted of nine SNPs

(minimum P = 9.36 × 10-24) located at the IL18 locus. The third region had only one genome-

wide significant SNP (rs13271361, P = 3.08 × 10-8), which was located within MROH6 on

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ntal MMMMatatatatererere iiial FiFiFFigugugurere S1SSS ) )) asasasas ccccovariaiiaiatettetessss ((c(cononffofof ununundedededersrsrs)))) innnn tttthhhehe aassssociaiaiaiatititiion anan lalalysyseses,

affect both IL-18181818 llllevellls anddd d SNSNSNNPPPs by yy dididid fffffff erences iini allllllele frfff eqqquencies and IL-18

llatiio ((FiFi 11))




9

chromosome 8. Out of the 110 significant SNPs, all but six were genotyped or successfully

imputed in the replication cohort, and all these SNPs replicated with P values ranging from 3.50

× 10-42 to 5.98 × 10-9 with the same direction of the effect (Supplemental Material Table S6). The

most significant SNP from the discovery cohort (kgp1626348) was located at position 32484955

on chromosomes 2. The overlapping variant in the replication, at this position, is rs67593209

(also known as chr2:32484952:D, or chr2_32484952_32484955) which is a TAAG/- deletion

polymorphism. In the replication cohort, this polymorphism replicated with very similar effect

on IL-18 levels as kgp1626348 in the discovery cohort (Supplemental Material Table S6).

Pooled analyses

Pooled analyses of the imputed data from the discovery and replication cohorts resulted in five

chromosomal regions being significantly associated with IL-18 levels (Figure 2, Supplemental

Material Table S7). In addition to the three previous regions, two SNPs in a region on

chromosome 5 (minimum P <5.00 × 10-12 for rs17229943) located in RAD17, and 17 SNPs

(minimum P = 1.38 × 10-8 for rs1842893) located upstream of CARD16, CARD17, and CARD18.

Including the top SNP from each of the five identified regions (rs385076, chr11.112034062=

rs34649619, rs17229943, and rs2290414, and rs1842893) as covariables in the conditional

analyses resulted in two additional signals, a second signal in NLRC4 (minimum P = 3.79 × 10-16

for rs149451729= exm184959) and a second signal in the IL18 region (minimum P = 1.66 × 10-

12 for rs11214115). Including also the two latter association signals in the conditional analyses

did not result in any significant results (Figure 2).

Bioinformatic analyses of top SNPs

Bioinformatic analyses were performed using the results from the pooled analyses with imputed

data. The most significant SNPs at the IL18 locus (Supplemental Material Figure 2A) were

Material Table S6)6)6)6)...

lyses of the imputed data from the discovery and replication cohorts resulted in

m n

a

m s

P 1 38P × 10 8 for rs1842893) located pstream of CARD16 CARD17 and CAR

lyseees s s ofofofof ttthehehee impmpmputed data from the discooovvverry and replicationonon cohorts resulted in

maaaal rrrer gions beininingg siiigggnifficiciccantllllyyy asssssociiiatted wwith hh ILILIL-1-1-1- 8 leleevelss (((Fiiguguure 2222, Suuuppppleeemmen

able SSS7)7)7)7). IIIn aaddddddititititioioi nn totot thehehe tttthhhhree ppprererevivviviououss reregigiionnonons,, tttwowowo SSSSNPNNPNPss iniii aaaa rrrreegegion n onon

me 5 ((minimum PPP <555.00000 P × 10101010-112 ffffor rs1117272722292929949494943)) lllocateddd iin RARARAR D1D1D1D1777, ,, and 17 SNPs

PPP 11 3388PP × 1010-8-8 ff 1s1848428289393)) llo tedd st ff CACARDRD1616 CACARDRD1717 dd CACAR




10

distributed throughout IL18 and the neighboring genes (TEX12 and BCO2). The most significant

SNP (chr11:112034962:I or rs34649619, P = 1.17 × 10-50) was located in a site which is enriched

for transcription factor binding (Figure 3; Supplemental Material Figure S2). This variant

together with neighboring sites (AGAAGCTT[-/A]ATTTATTTTAC) match the DNA motif for

among others: FOXD3 (TTATT), FOXA2 (TATTT), and FOXI1 (TATTT) for the wild type

allele (-). The disruption of a binding site by the alternative (minor) allele agrees with lower

levels of IL-18 in patients with the alternative allele (Table 1, Supplemental Material Table S7).

The additional association signal from the conditional analyses was centered upstream and in the

beginning of IL18 (Supplemental Material Figure S2). Two of the SNPs (rs360717 and

rs360718, of which rs360718 as the most significant site in the conditional analyses, P = 2.03-12)

were located in a site enriched for transcription factor binding in association with the

transcription start site (Figure 3, Supplemental Material Figure S2).

The association signal at the NLRC4 locus consisted of a large number of SNPs in strong

linkage disequilibrium (Supplemental Material Table S7; Figure S3). This signal included

NLRC4, but also DPY13, SPAST and SLC30A6. The most significant SNP (rs385076, P = 6.99 ×

10-72) did not have a considerably lower P value compared to the others (second most significant

P = 2.78 × 10-68) nor a greater genetic effect (0.113 units of the log transformed IL-18 values in

ng/L, compared to 0.108 for the second largest). However, rs385076 is the only SNP that is

located in a predicted regulatory region. The region around rs385076 has been predicted to be an

active promoter in GM12878 (B-lymphocyte, lymphoblastoid) cells and a weak promoter in

HepG2 (hepatocellular carcinoma) cells and is also located close to the transcription start site.

One of the most significant SNPs at NLRC4 (rs212717, P = 4.27 × 10-67) was an eQTL

(expression quantitative trait locus) that associated with the expression of NLRC4 (P = 4.037 ×

entered upstream anananandd dd

Ps (rs363636360707070717171717 andddd

o

e

o

e s

eq ilibri m (S pplemental Material Table S7; Fig re S3) This signal incl ded

of wwwhihihih chchchch rrs3s33s3600071777 8 as the most significantntnt ssite in the conditititiooonal analyses, P = 2.P

edd d innn a site enriiiicccheddd ffffor ttttrrar nscrccrippptiion faactoorr bindndndininingg innn aassociiiatiiiooon witiii hhh h tthheee

n starararttt t sisisisitetete (FiFiFigugugurere 333, Supppppplelelelementntntallalal MMMMattttereriiaial FFFigigigigururureee S2S2S2)))).

e association signgg alll at thhhhe NLNNLRCRCRCC444 lllocus con iisiisted of f a llal rggge numbbbber of SNPs in sd

iililibbrii ((SS lle nt lal MMat iiall TT bablle SS77; FFiig S3S3)) TThihi isi lal ii ll ddedd




11

10-7) in Epstein-Barr virus–transformed lymphoblastoid cell lines 25 (data retrieved from

eqtl.uchicago.edu, April 16, 2013). The second signal at the NLRC4 locus, which was identified

in the conditional analyses, was driven by rs149451729, which is located in exon 6 of NLRC4.

This SNP is a rare (minor allele frequency [MAF] = 0.0037) missense variant (also known as

2357G>T) resulting in the amino acid substitution from glycine to valine at position 786 of the

protein (Gly786Val). Both SIFT 23 and PolyPhen 24 predictions (SIFT score = 0.04, PolyPhen

score = 0.943) suggest that this amino acid change is deleterious and therefore likely to impact

the function of the protein.

The association signal on chromosome 8 consists of 14 SNPs located within GSDMD and

MROH6 as well as between the genes (Supplemental Material Figure S4). While the most

significant SNP (rs2290414, P = 2.77 × 10-16) was located in a non-regulatory and non-coding

region of GSDMD, two of the top five SNPs (rs13254352, P = 5.88 × 10-14 and rs13271361 P =

9.49 × 10-16) were located in predicted regulatory regions within MROH6. The association signal

on chromosome 5 consisted of two SNPs neither of which were found to be associated in the

initial GWAS in the discovery cohort. The most significant SNP (rs17229943, P = 7.04 × 10-12)

was located in an intron of RAD17, in a region where no functional element has been assigned.

The second region on chromosome 11 included as set of 18 SNPs with P values ranging

from 1.10 × 10-8 to 3.06 × 10-8 (Figure 4, Supplemental Material Table S7). None of the SNPs in

this region were identified in the GWAS of the discovery cohort only. All SNPs were located

upstream of a cluster of CARD (CARD16, CARD17, and CARD18) and CASP (CASP1, CASP5,

CASP4, CASP12) genes, except for one which was located upstream of all but CARD18

(Supplemental Material Figure S5). Some of these SNPs (e.g. rs17103763 and rs11226633) were

located in predicted regulatory regions close to transcription factor binding sites. In previous

ocatet ddd d iiiwiththththiiini GSGSGSGSDMDMDMDM

d

G 1

6

some 5 consisted of t o SNPs neither of hich ere fo nd to be associated in th

welelelell l l l asasas bbbetettetweweweenenen the genes (Supplementttalalaa Material Figgguree S4SSS ). While the most

SSNSNP P (rs22904441444, PP = 2.77.77 P × 110---1666) wawwas looccateedd d ininin aa nnnon-reeggulatatatory ananana d nnnon---cood

GSDMMMMDDDD, tttwo oofff thtththee ttotop p fiiveveve SSSSNPsss (r(r(rs1ss1s1323232254545543535353 222, PPPP === 5.888888 8PPPP ××× 10101010-14444 aaaandndndd rs111322323271711713636361

6)) were located iiini pppredididiict deddd regggulllatory yy regigiions wiiii hthhiniii MRMMROHOHOHOH6. ThThThThe association

55 iist ded fof t SSNPNP iithhe fof hihi hch ffo dd to bb iciat ded iin thh




12

studies, SNPs with somewhat lower Ps in our study (e.g. rs17103597, P = 6.06 × 10-6) have been

identified as eQTLs (P = 2.81 × 10-118) for CARD16 26 whereas SNPs (e.g. rs1941425) that have

previously been identified as eQTLs for CASP1 27 were not associated with IL-18 levels in our

study (P > 0.05).

Pairwise genetic interactions

We also tested for pairwise genetic interactions between the top SNPs at each identified loci.

One of the strongest associations was the SNPs in NLRC4 gene. NLRC4 is known to interact

with other proteins including CASP1 and NOD2. However, we did not see any genetic

interaction between the SNP in the CASP1 region and the SNPs in NLRC4 (P > 0.05). Similarly

we did not find any significant interaction between any of the top SNPs tested (P > 0.05). NOD2

is located on chromosome 16: position 50,727,514-50,766,987 (build 37/hg19). In this region

(10kb upstream and 10kb downstream of NOD2), we had included 192 SNP in our analyses. Of

these, the most significant P-value was 0.0117. This is not significant after adjusting for the 192

SNPs tested in the region.

Multiple regression analyses

The multivariable model, including the seven top SNPs from the pooled analyses, resulted in

similar beta estimates and P values as in the original GWAS (Table 1). The total variance

explained by each of the SNPs range from 0.33 % to 3.2 % of the variation in IL-18 levels and

altogether they account for up to 8 % of the total variance in IL-18 levels.

Population stratification

Since our study includes individuals with different genetic backgrounds (Supplemental Material

Figure S1), we included the first four principal components in all analyses. This resulted in

lambda values (inflation factor) of 1.03, 1.10, and 1.16 in the discovery, replication and pooled

t see any geg netic

RC444 ((((PPPP(( >>>> 0000.05050505).).).) SiSiSiSimmmmi

f N

on chromosome 16: position 50,727,514-50,766,987 uild 37/ 19 In this regi

r

m e

d in the region

find d dd anananyy y sisisisigngg ififificicicicant interaction betweennn aaanny of the top p SNNPsPsPsP tested (P( > 0.05). N

nn n chhhromosome 16:: ppposititititiioi n 5050505 ,777227,555114-5500,76666,6,6,9989 77 7 ((bbuuildd 3337//hghghgg19)).).) IIIIn thhhhis rreegi

ream aaandndndnd 1110kkkbbb dddodownwnsstreamammm of NONONONOD2D2D2D2)))), wee hahahh d dd ininininclclcluuudedededd 1111929292 SSSSNPNPNPNP iiinnn ouurr ananalallysyse

most signgg ificant PPP-v llalue was 000 0.0001111111 77. TThihihih s isii not sigiigi niiiifififif cant aftfff er adjdjd ustinggg for the

ddd iin thhe iio




13

datasets respectively (estimates are based on genotyped SNPs only). The lambda value for the

combined data (discovery + replication cohort) increased slightly (1.16), which can be explained

by the strong associations between IL-18 levels and multiple SNPs (Supplemental Material

Figure S6). However, we also performed sensitivity analyses by stratifying the analyses to

include only individuals with European, only African or only Asian descent. The European-only

analyses gave similar results to the previous analyses whereas the results with patients from the

other ethnicities were too few (N=53 and N=95 with both genotype and IL-18 levels measured)

to give any significant results (Supplemental Material Table S8).

Serial IL-18 measurements and ACS subtype analyses

In a subset of the patients with genotype data (N=3,080) IL-18 was also measured at a second

visit. For these patients, the IL-18 levels were higher (P < 2 × 10-16) at the second visit (mean =

306.0 ng/L, median = 341.3 ng/L) compared to baseline (mean = 258.1 ng/L, median= 231.0

ng/L). The seven identified SNPs were also associated with IL-18 levels at the second visit. All

beta estimates were numerically larger at the second visit compared to baseline, however a test

for the paired difference was only significant for two SNPs (Table 1). In order to evaluate the

variable effect of the IL-18 associated genetic variants in different ACS subtypes, additional

analyses were performed separately for patients with STEMI (ST elevation myocardial

infarction), NSTEMI (Non-ST elevation myocardial infarction) and unstable angina. The IL-18

levels were similar between the ACS subtypes with mean [interquartile range] log transformed

IL-18 levels of 5.46 [5.20-5.49] for unstable angina, 5.48 [5.21-5.48] for STEMI and 5.45 [5.18-

5.46] for NSTEMI. For the most significant SNP (rs34649619) in the IL18 region, the effect of

the SNP appears to be more pronounced in patients with STEMI as compared to NSTEMI (Table

1). However, the interaction between the rs34649619 and ACS subtypes is week (P = 0.0397),

o

h e

,

t

ates ere n mericall larger at the second isit compared to baseline ho e er a

of tttheheheh pppatatatieieieenntn ss wiwww th genotype data (N=333,080808080) IL-18 was allllsososo measured at a seco

heeeseeee patients, tthehehe IL-L-L-188 lllleeve elsss weeerre hhhiggherr ((P( <<< 2222 × 1000-116) aat theee seconononond ddd viviviisit (mme

, mediddidianananan = 3414141 333.3 nn //g/g/L)LL comomommpared ddd tototo bbbbasselelliinine (((mmmeanan = 252525258.88 111 nnng/L/L/L/L, mmmedididianan= 2323231

seven identifiedddd SSSNPNPNPs were allsl o asso iciiiat deddd with ILIL-1818181 llllevelllls at thhehh second visit

at iri llll lla t hth dnd iisiit dd to bb leliin hh




14

and is not significant after adjusting for testing seven SNPs.

Discussion

We have performed a GWAS to identify genetic variants influencing IL-18 levels. In total we

identified and replicated three loci (IL18, NLRC4 and MROH6) of which IL18 and NLRC4 each

have two independent effects. By combining data from the discovery and replication cohorts,

two additional association signals were identified. The association between IL18 and the mature

form of the protein it codes for is not surprising and has been identified in previous GWAS 28, 29.

However, the identification of two independent variants, located in different regulatory regions,

is a novel finding. In addition, we identify that one of these variants interrupts a binding site for a

number of transcription factors including FOXD3, FOXA2, and FOXI1.

The strongest genetic effect influencing the IL-18 levels was seen for the NLRC4 locus.

A recent GWAS also identified SNPs near NLRC4 to be associated with IL-1ra as well as IL-18

28. However, in our study, we also demonstrate that the association signal for IL-18 reflects one

regulatory and one deleterious variant within NLRC4. The NLRC4 protein belongs to the Nod-

like receptors (NLRs). NLRC4 is an inflammasome that activates the inflammatory cascade in

the presence of bacterial molecules. NLRC4 recruits and activates procaspase-1, which in its turn

is responsible for the maturation of pro-IL-18 30. In our study, we identify one variant that

regulates the expression of NLRC4 and another variant that alters the amino acid sequence of the

protein resulting in loss of function. It has been suggested that the expression of another NLR,

NLRP3, is activated in patients with coronary artery disease (CAD) followed by increase in IL-

18 levels 31. Our finding also suggests that the NLRC4 inflammasome is also an important

complex for IL-18 maturation in patients with ACS, and thereby regulates the release of IL-18.

IL-18 is regarded as a risk factor for ACS, by promoting atherosclerosis7 and, consequently, the

p

fferennnntt t t rerereregugugugulalalalatotototoryryryy rrrregegegegii

inding. In addition, we identify that one of these variants interrupts a binding sit

t

e o

W I

r, in our study, g s

indingng.... InInI aaaddd itittion, we identify that one ofof these variants innntett rrupts a binding sit

trrrannnscription faffaccctorors ininini clclclcludududu inininngg FOFFOF XDXDXDD33, FFOOXA2A2A2, anand dd FOFOFOXIXIXX 111.

e stttrorororongngnggesesest t t gegegeg nnen titititic c c efffffefeffecttt inininflflflflueueuu nccccininng g g g thhhe e e e ILILILI -1888 llllevevevevelelellssss wawawaw ssss sseseeenenenen fffforororor ttthehehehe NLNLNLN RCRCRCRC4 lllo

WAS also identntntntifififi ieieieeddd d SNSNSNNPsPsPs nnnneaeaear rrr NLNLNLNLRCRCRCRC4444 tototo bbbbe ee assosososociciciiatatatatededd wwwwitititth hh ILILILIL---11r11 a as well as I

r,r, iinn ouourr ststududdy,y, wewe aalslsl oo deddemomonsnstrttratatee ththt atatt ttthehe aassssocociaiatititionon ssigignanall fofforr ILILL-1-1-11888 rereflflecectsts




15

NLRC4 inflammasome is also likely to play a role in the etiology of the disease. We suggest that

genetic variants that decrease the activity or the expression level of NLRC4 could be protective

of atherosclerosis. In our study we have identified one deleterious missense variant that

decreases IL-18 levels and one regulatory genetic variant that decreases the expression of the

NLRC4 resulting in decreased IL-18 levels. Recently, a de novo missense mutation that affects

the nucleotide-binding domain of the NLRC4 inflammasome was shown to cause early-onset

recurrent fever flares and macrophage activation syndrome 32. In contrast to the deleterious

variants that we identified, this de novo missense mutation was associated with spontaneous

inflammasome formation and production of IL-18. We can therefore conclude that the

importance of the NLRC4 inflammasome in IL-18 production is not restricted to ACS patients.

The NLRC4 inflammasome consists of a number of different components of which most

have a “caspase recruitment domain” or CARD 33. Therefore, another interesting finding in our

data was the association of SNPs upstream of CARD16, CARD17 and CARD18 (also known as

COP1, INCA and ICEBERG). These CARD genes are located close to the gene encoding

procaspase-1 (CASP1) and are likely to be the result of an historical duplication event followed

by the accumulation of mutations changing the functionality of the proteins 34. These genes

encode caspase inhibitors that bind to and interact with procaspase-1, resulting in inhibition of

procaspase-1 activation. In agreement with this, CARD16, CARD17 and CARD18 have been

shown to prevent at least IL-1 release. However, in this study we cannot distinguish which

gene(s) are regulated by the SNPs identified, and clusters of genes with similar functions often

share expression patterns. Even though expression data show that our association overlaps with

an eQTL for CARD16, it is possible that these variants influence the expression of the whole set

of CARD and CASP genes in the region. Two additional association signals are located around

ated with spop ntaneoeoeoeou

onclull deddd thththth tttat tttthhehh

e

e

n

w

CA and ICEBERG) These CARD genes are located close to the gene encoding

of fff ththththeee NLNLNLN RCRCRRC4 4 4 4 inflammasome in IL-18 ppprodo uction is not rererestss ricted to ACS patie

e NLNLNLN RC4 inflaammmm aasomeee e consnssiisi ttts of aaa nnumbmberr oof f f dididiffereerent cocoompmpmpponennnntststs ooof f ff whhhhicch

pase rerereecrcrcrcruitmmenentt tt dodod mam in””” orororor CARARARA DDDD 333333. ThThTTheerefefefooorore,ee, anoooththththerer iiinnteresesesestititing fffiinindididdingng iiin

e association of fff SNSNSNSNPsPP upspp tream foff CACACAC RDRDRD161616,,, CARDRDRD1717171 anddd777 CACACAC RDRDRD18 ((also know

CACACA dd ICICEBEBERERG)G) ThTh CACARDRD ll at ded llo t hth dodiin




16

the genes MROH6 and RAD17. Neither of these genes has previously been associated with any

inflammation or cardiovascular phenotypes.

The datasets we have used are genotyped using two different arrays. The replication array

includes a large number of SNPs that have been selected to be nonsynonymous coding variants

and also includes less common variants. In combination with using a large dataset and the latest

release of the 1000 genomes reference panel for the imputations, we have also been able to

evaluate the effect of rare variants. This has resulted in the identification of a rare non-

synonymous deleterious variant in NLRC4 that is associated with decreased IL-18 levels. It has

been suggested that rare variants might have larger effects on complex phenotypes compared to

common variants that have traditionally been identified in GWAS 35. The effect of the rare

NLRC4 variant (rs149451729) on IL-18 levels was large, with an average decrease of almost one

standard deviation for individuals being heterozygous (average log transformed IL-18 [units of

ng/L]= 5.03, ) for the variant compared to homozygous for the common allele (average log

transformed IL-18 = 5.46). Owing to its frequency, this variant explains less than one percentage

of the total variation in IL-18 levels in the sample. Altogether, the identified loci explain

approximately 8% of the total variance in IL-18, which is more than any of the clinical

covariables included in the analyses.

There are some limitations of this study. The study samples represent a global selection

of patients, which might give rise to population stratification. To resolve this problem we have

included the first four genetic principal components in all analyses. This indicated very limited

levels of inflation. In addition we have performed subgroup analyses of the major population

groups, which resulted in very similar results to the analyses in the total cohort. It is also worth

noting that even if we have performed a two-stage GWAS with one discovery and another

eased IL-18 levelssss. .. ItI

x phenotttyt pes compmpmppaaaare

a 35

r o

eviation for individuals being heterozygous (average log transformed IL-18 [unit

3, ) for the variant compared to homozygous for the common allele (average log

d IL 18 5 46) O ing to its freq enc this ariant e plains less than one perce

ariaaaantntnts s ththththatatat hhhhavvveee traditionally been identttififififieied in GWAS 35. TTTThe effect of the rare

riaanannttt (rs1494517171729) oon IIIIL-LLL 18888 lllevvveels wawwas llarrge,e wwwwititi hh h annn averaraageee ddddecreeeeaaaseee ooof aaalmlmml o

eviatitiitionononn ffffooor indnddiivividididuaualsll beieieingngngng heterererozozozozyyygy ououss (a(a(( veveveerararagegege logogogg ttttraransnsformrmrmmedededd IL-LL 1811818 [[[[ununit

3,, )) for the variant compapp reddd d to hhhhomozygygygous ffof r thhhe common alllllllelllle (a( veragegg loggg

ddd ILIL 1188 55 4646)) OO iin to iits ff hthiis iri t lpl iai ll hth




17

replication cohort; some of the results from this study were identified in the combined sample

set. These include the independent genetic variants in IL18 and NLRC4, as well as the genetic

variants in RAD17 and close to the CARD-genes.

One of the most interesting results of our study is that NLRC4 plays an important role in

regulation of IL-18 levels in patients with ACS. However it should be recognized that the lack of

association between genetic variants in other genes (e.g. NOD2 and CASP1) does not suggest

that they are not involved in IL-18 production. One possibility is that there are no genetic

variants that influence NOD2 and CASP1 in our study and therefore we do not identify

significant associations with genetic variants in these genes. Another limitation with the study is

that we cannot evaluate the importance of IL-18 and NLRC4 on development and progress of

ACS. Previous studies in animal models suggest that IL-18 might have a causal effect on

arteriosclerotic plaque formation. Recently, Mendelian randomization studies have been used to

evaluate the causal effect of biomarkers on risk of disease, using genetic variants as instrumental

variables. However, the individual genetic variants identified in our study explains only a small

fraction of the variability in IL-18 levels, and therefore a much larger sample size and/or a long

follow up would be needed in order to assess the causal effect of NLRC4 genetic variants and

IL-18 levels on ACS.

In summary, we have identified common and rare genetic variants that are associated

with IL-18 levels. Our results highlight the importance of the NLRC4 inflammasome, and

proteins involved in caspase-1 activation, for IL-18 production in patients with ACS. IL-18 has

previously been suggested to promote atherosclerotic plaque formation and a better

understanding of the mechanism behind the increased IL-18 levels in patients ACS should be of

significant value in understanding the disease progression and for developing more effective

we do not identifyyy

imitatititition witititithhh h thththheeee ststststu

n

i

otic plaque formation. Recently, Mendelian randomization studies have been us

e m

Ho e er the indi id al genetic ariants identified in o r st d e plains onl a s

nnottt eeevavavalulululuatattateee thththheee importance of IL-18 annnd d dd NLNN RC4 on develelelooopment and progress

ioouo ssss studies in aaanimamaal momomom delssss suuugggessst tthat IIL-181181 mmmmighthht havvee a caaausalalalal eeeffffect onoon

otic ppplaalalaquququq e fofof rmrmatattiioion.n RRecececenenenently, MMMMennnnddedelilillianan ranananndoddodommmizazazatitititionon ssttutt didididieseeses hhhhavvee bbbebeenen us

e causal effect off ff bibibibiomarkekk rs on iriiskkk offf f dididid sease,,, usiinggg gggenetiiici variiaii nts as instrum

HoHH thhe ii dndii idid ll iti iri ts iiddentififiiedd iin t dd llaiin ll




18

treatments.

Acknowledgments: Genotyping was performed by the SNP & SEQ Technology Platform in

Uppsala, which is supported by Uppsala University, Uppsala University Hospital, Science for

Life Laboratory (SciLifeLab) Uppsala and the Swedish Research Council (Contracts 80576801

and 70374401). The computations were performed on resources provided by SNIC through

Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) under

projects p2012253 and p2012095. Ebba Bergman PhD at Uppsala Clinical Research Center,

Uppsala, Sweden, provided editorial assistance.

Funding Sources: The PLATO study was funded by AstraZeneca. The genetic work was also

cofunded by the Swedish Heart-Lung Foundation.

Conflict of Interest Disclosures: Å Johansson and N Eriksson have received institutional

research grant from AstraZeneca. RC Becker has received grants from AstraZeneca been

scientific advisory board member for Bayer, Jansen, and Regado Biosciences, and safety

monitoring committee member for Portola. RF Storey has received institutional research grants

from AstraZeneca, Daiichi Sankyo/Eli Lilly, and Merck; consultancy fees from AstraZeneca,

Accumetrics, Correvio, Daiichi Sankyo/Eli Lilly, Merck, Plaque Tec, Roche, The Medicines

Company, Regeneron, and Sanofi-Aventis; speakers fees from AstraZeneca, Accumetrics, and

Daiichi Sankyo/Eli Lilly; travel support from AstraZencea; consumables from Accumetrics; and

honoraria from Medscape. E Hagström has received institutional research grant from

AstraZeneca; honoraria from Sanofi. C Varenhorst has received research grant from

AstraZeneca; speaker fees from AstraZeneca and The Medicines Company, and is Advisory

Board member for The Medicines Company and AstraZeneca. SK James has received

institutional research grant from AstraZeneca, Terumo Inc, Medtronic, and Vascular Solutions;

honoraria from The Medicines Company and AstraZeneca; and consultant/advisory board fees

from AstraZeneca, Dachii Sanchio, Janssen, Medtronic and Sanofi. HA Katus has received

honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Roche, and Bayer; and holds a

Troponin T Test Invention patent jointly with Roche and receives royalties for this patent. Dr.

Steg has received personal fees and non-financial support from AstraZeneca; personal fees from

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19

Amarin, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck

Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, Medtronic, Vivus, The Medicines Company,

Sanofi, Servier, and GlaxoSmithKline for steering committees, data monitoring committees,

event committees and consulting activities; PG Steg's institution receives research grants from

Sanofi and Servier and he is a stockholder in Aterovax. L Wallentin has received research grants

from AstraZeneca, Merck & Co, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer,

GlaxoSmithKline; and he act as consultant for Abbott, Merck & Co, Regado Biosciences, Athera

Biotechnologies, Boehringer-Ingelheim, AstraZeneca, GlaxoSmithKline, and Bristol-Myers

Squibb/Pfizer; lecture fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers

Squibb/Pfizer, GlaxoSmithKline. L Wallentin has also received honoraria from Boehringer-

Ingelheim, AstraZeneca, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline; travel support from

AstraZeneca, Bristol-Myers Squibb/Pfizer and GlaxoSmithKline. A Siegbahn has recieved

institutional research grants from AstraZeneca, Boehringer-Ingelheim and Bristol-Myers Squibb.

BJ Barratt and A Himmelmann are employed by, have stock and stock options in, AstraZeneca,

the PLATO trial sponsor. BJB and AH do not consider that this creates any conflict of interest

with the subject-matter of this publication.

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q

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andndndd A Himmemelmlmlmanann n n ararreee eeempmpplololoyyyedd bybybyy, haavee stottockckckk aandndndd sstootockckck opttptioioioionsss iiiin,n,n AAAAstststrararaZZeZZ n

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S Neale B Todd Bro n K Thomas L Ferreira MA Bender D et al Plink: A t

sooonnn n KL, Steememeers FJJJ,J LLLLeeee GGGG, MeMM nndoooza LGLG, ChChCheeeeeeee MMMSSS. A ggennnomomome-wiwiw ddded scccalaaabbblb e aassssssayayay usingngngg mmicrooarrrray y y tetechnonoloooggyg . NNNat GGenenen tt. 20202 0555;3337:5549-55555554.

rs FJ, Chang WWWW, ,,, LeLeLeeeee e G,G,G,G BBBararararkekekek r r r r DLDLDLDL,,,, ShSShS enenen RRRR,,, GuGG ndndndn erererersososos n nnn KLKLKLKL. WhWhWhWholooo e-genome with the singggle-bbbab se extension assayyy. NaNN t MMeM thodddds. 2020202 0606066;3;33 33:31-33333333.

SS NNe lal BB TT doddd BBr KK TThho LL FF iir MAMA BBe dnd DD et ll PPlili knk AA t




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A, Borkkkk PPPP, tttet alll.l AAAA mmmme2010000;7;7;7;7:2:2:2:248484848 222249494949

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Te

AL Liang L Moffatt MF Chen W Heath S Wong KC et al A genome ide

er BBBEEE,E Nica a ACACACAC,,, Foooorrrrrrrresesestttt MMMS,S,S,S, DDDimimimimasasass AAAA,, Biirdd CCCP,P,P,P, BBBBeaaaazlzlzlz eyeyey CCC, et aaaal.l.l.l. PPPopopopo ullulatatatatioioionnnnof ff huuuman gene eeexprereessiooioonn.n NaNaNatt GeGGenettt. 200707;39:9:1212121217-112224.

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ALAAL LiLi LL MM fofffatt MMFF CChhe WW HH hth SS WWo KKCC t lal AA iidde




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23

Table 1: SNPs identified in the GWAS

SNP Gene MAF* Beta† SE beta P Variance‡Subgroup analyses:

Only patient with a measurement form the second visit is included. N=3080

Subgroup analyses:Effect of SNPs in ACS subtypes.

BaselineBeta (P)

Second Visit

Beta (P)

Second-Baseline§Beta (P)

STEMI (N=3577)Beta (P)

NSTEMI (N=3837)Beta (P)

Unstable angina

(N=1761)Beta (P)

rs385076 NLRC4 0.39 0.1089 0.0061 1.5 × 10-70 0.0318 0.113(1.6 × 10-26)

0.120(7.7 × 10-32)

-0.007(4.5 × 10-1)

0.100(2.0 × 10-16)

0.112(2.0 × 10-16)

0.117(4.1 × 10-14)

rs149451729 NLRC4 0.0037 -0.4069 0.0482 3.2 × 10-17 0.0062 -0.361(3.6 × 10-5)

-0.515(9.6 × 10-10)

0.154(4.1 × 10-2)

-0.360(3.3 × 10-6)

-0.400(3.6 × 10-9)

-0.518(9.6 × 10-4)

rs34649619 IL18 0.23 -0.1276 0.0075 1.3 × 10-64 0.0227 -0.130(6.7 × 10-24)

-0.142(4.9 × 10-30)

0.011(3.0 × 10-1)

-0.150 § (2.0 × 10-16)

-0.110 ||(2.0 × 10-16)

-0.122(1.9 × 10-10)

rs360718 IL18 0.28 -0.0505 0.0071 1.2 × 10-12 0.0049 -0.048(1.1 × 10-4)

-0.053(8.0 × 10-6)

0.005(6.2 × 10-1)

-0.060(8.5 × 10-8)

-0.054(6.4 × 10-7)

-0.026(1.4 × 10-1)

rs17229943 RAD17 0.062 0.1020 0.0146 2.7 × 10-12 0.0046 0.076(2.0 × 10-3)

0.085(3.5 × 10-4)

-0.009(6.8 × 10-1)

0.093(6.3 × 10-5)

0.113(1.4 × 10-7)

0.116(3.1 × 10-3)

rs2290414 MROH6 0.45 -0.0515 0.0060 1.7 × 10-17 0.0067 -0.047(7.7 × 10-6)

-0.067(2.5 × 10-11)

0.021(2.3 × 10-2)

-0.056(3.3 × 10-9)

-0.052(1.9 × 10-8)

-0.052(8.3 × 10-4)

rs11226633 CARD18 0.25 0.0407 0.0069 3.7 × 10-9 0.0033 0.039(1.2 × 10-3)

0.051(1.1 × 10-5)

-0.012(2.5 × 10-1)

0.029(6.9 × 10-3)

0.053(6.4 × 10-7)

0.032(5.9 × 10-2)

* MAF - minor allele frequency. † Beta = increase in the log transformed IL-18 value per copy of the minor allele‡ 8% of the total variance in IL-18 levels can be explained by these SNPs§ Effect on the difference between IL-18 levels at the second visit and the levels at baseline. || Nominally significant interaction with treatment (P = 0.0397) between STEMI and NSTEMI patients.

00000000-32-32-32-32) )))

-0.000 0007777(4(4(4(4.5.5.5.5 ×××× 11110000-11))))

0 361 0 515 0 1540482828282 3.3.3.3 2 222 × 11101 -17 0.0062 -0..36333 1(3.6 ×× 10-5)

-0.511115555(9.6.66.6 × 11110000-10)

0.154(4.1 × 10-2)

0000075757575 1.1.1.1.3 3 3 3 × 1000-6444 0.0.0.0.0202020227272727 -0...13000(6(6(66 7.777 ×××× 1111000-24-24-24-24) )))

--0.14422(4(4(4(4 9.999 ×××× 11110000-30) )))

00.0 01011(3(3(3(3.000 ×××× 1110000---1- )) ))

000007171 1.1..2222 × 10100-1212 0.0.0.0000000494994 -0.0.0.040404888(1(1(1(1.1.1.1.1 ×××× 11110-4-4-4) ))

-0.0.0.050505333(8(8(8(8.0000 ×××× 11110000-6-6-6- ) )))

0.0.0.000000555(6(6(6(6.2.2.2.2 × 10-1)




24

Figure Legends:

Figure 1: Directed acyclic graph (DAG) of the variables that were identified as potential

confounders or precision variables to be used in the GWAS. The precision variables that are

influencing IL-18 but not the SNPs are LLA (lipid lowering agent at day of randomization),

CRD (history of chronic renal disease), diabetes (medical history of diabetes mellitus), PAD

(History of peripheral arterial disease), BMI (body mass index), sex and age. The confounding

variables are the principal components (PCs) that affect SNPs and IL-18 levels.

Figure 2: Manhattan plot of –log(P) from the GWAS in the pooled replication and discovery

cohorts where A) is the primary pooled analyses, B) is the conditional analyses adjusting for

rs385076, rs17229943, rs2290414, and rs34649619, C) is the conditional analyses when also

adjusting for rs149451729 and rs360718, and D) is the conditional analyses adjusted for all

seven SNPs.

Figure 3: Location of the two independent SNPs in the IL18 promoter region in relation to

transcription factor binding (Transcription Factor ChIP-seq from ENCODE) in different cell

types.

Figure 4: Manhattan plot over the CASP and CARD region on chromosome 11.

18 levels.

M e

e o

rs17229943, rs2290414, and rs34649619, C) is the conditional analyses when als

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s

Mannnhahahah ttttttananan ppplooot t t ofooo –log(P( ) from the GWAAAS SS in the pooled reeplppp ication and discove

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rs17222222299999999434343, rsrs222222290909041441414, anddndnd rs34646464 494949496161616 9,9,99, CCCC) ))) isisis tttthehhehe ccconnndidididitititit ononala ananananalylylysess hwhwhenen aals

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s



Gabriel Steg, Ann-Christine Syvänen, Lars Wallentin and Agneta SiegbahnKatus,Hagström, Christoph Varenhorst, Tomas Axelsson, Bryan J. Barratt, Stefan K. James, Hugo A.

Åsa Johansson, Niclas Eriksson, Richard C. Becker, Robert F. Storey, Anders Himmelmann, EmilAcute Coronary Syndromes: A Genome-Wide Association Study in the PLATO Trial

The NLRC4 Inflammasome Is an Important Regulator of Interleukin-18 Levels in Patients with

Print ISSN: 1942-325X. Online ISSN: 1942-3268 Copyright © 2015 American Heart Association, Inc. All rights reserved.

TX 75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas,Circulation: Cardiovascular Genetics

published online March 6, 2015;Circ Cardiovasc Genet.

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1

SUPPLEMENTAL MATERIAL Table S1. Genotyping, Imputations and QC Discovery cohort Replication cohort Pooled cohort Illumina BeadChip HumanOmni2.5-‐4v1 (Omni2.5) Infinium HumanOmniExpressExome-‐8v1 No patients genotyped 3998 6015 Sample QC Call rate > 98%, duplicates, gender check Samples that passed QC 3982 5996 9978 Samples that passed QC with IL-‐18 measurements 3777 5563 9340

SNP QC for Principal Component analyses Call rate > 98%, MAF > 0.01 and HWE (p > 1 × 10-‐8) Number of SNPs in MDS 1,586,429* 125,003 † 119,547† Pre-‐Imputation SNP QC Call rate > 98%, MAF > 0.001 and HWE (p > 1 × 10-‐8). Number of SNPs included in the imputations 1,796,367 705,132 Number of imputed SNPs 25,030,450 26,719,315 Post-‐Imputation QC MAF>0.003, HWE P-‐value > 10-‐10, and IMPUTE2 s Info metric > 0.3 Imputed SNPs that passed QC 12,176,855 12,158,950 12,013,605‡ * These were included in the primary GWAS in the discovery cohort. † In the replication cohort and in the pooled data, LD pruning (pair-‐wise LD <0.2) were performed prior to PCA. ‡ SNPs that overlap between the discovery and replication cohort, and pass the QC in the pooled dataset

2

Table S2. Simple linear regression using one explanatory variable and IL-‐18 as dependent variable. Variable P Sex 4.5 × 10-‐16 Weight (kg) 1.1 × 10-‐15 BMI [Kg/m2] 7.8 × 10-‐10 Medical History of Diabetes Mellitus 2.5 × 10-‐8 History of Peripheral Arterial Disease 1.2 × 10-‐5 Age [years] 4.5 × 10-‐5 History of Chronic Renal Disease 5.6 × 10-‐4 Lipid Lowering Agent on Day of Rand. 0.012 History of Myocardial Infarction 0.021 History of Asthma 0.024 Heparin during Index Hosp. 0.039 Smoking Status 0.093 History of Congestive Heart Failure 0.127 History of Dyspnea 0.153 History of Non-‐haemorrhagic Stroke 0.230 Ethnicity 0.231 History of Angina Pectoris 0.272 Revascularisation History of Prior CABG 0.275 History of Gout 0.292 Beta Blockers on Day of Rand. 0.333 History of Dyslipidemia including Hypercholesterol 0.376 History of Chronic Obstructive Pulmonary Disease 0.413 History of Transient Ischemic Attack 0.476 Calcium Channel Blocker on Day of Rand. 0.489 ASA on Day of Randomization 0.514 Glycoprotein IIb/IIIa during Index Hosp. 0.620 ACE Inhibitors on Day of Rand. 0.622 Treatment 0.654 Revascularisation History of Prior PCI 0.690 Final Diagnosis of Index Event 0.696 Angiotensin II Receptor on Day of Rand. 0.736 History of Hypertension 0.847 TIMI Risk Score STEMI (8-‐14)/NSTEMI (0-‐7) 0.901

3

Table S3. Multiple linear regression using all significant (P<0.1) variables from the simple regression model as explanatory variables and IL-‐18 as dependent variable. Variable Estimate SE P Age [years] -‐0.002 0.001 0.012 Sex [male] 0.127 0.020 1.3 × 10-‐10 Weight [kg] 0.000 0.001 0.69 Body mass index (BMI) (kg/m2) 0.009 0.003 0.0061 Smoking status (Ex-‐smoker/never smoker) -‐0.032 0.018 0.082 Smoking status (Habitual/never smoker) -‐0.004 0.018 0.826 Medical history of diabetes mellitus 0.077 0.017 5.406 History of myocardial infarction 0.023 0.017 0.189 History of peripheral arterial disease 0.098 0.027 2.3 × 10-‐4 History of chronic renal disease 0.100 0.037 0.0066 History of asthma -‐0.069 0.042 0.101 Heparin during index hosp. 0.019 0.014 0.175 Lipid lowering agent on day of randomization -‐0.055 0.017 0.0014

4

Table S4. Demographics for the discovery and replication cohort. Chi-‐squared contingency table tests were used to calculate P-‐values. Category Variable Outcomes Fraction P

Discovery Replication

Randomized treatment Randomized treatment Clopidogrel 50.1% 50.0% 0.93 Demographics

Ethnic origin African 0.53% 0.60% 0.51 Asian 0.78% 0.99% European 98.7% 98.4%

Sex Male 68.8% 69.9% 0.28 Smoking status Ex-‐smoker 26.1% 25.3% 0.61

Habitual smoker 35.2% 35.1% Non-‐smoker 38.7% 39.6%

Diagnose Final diagnosis of index event Other 1.71% 1.90% 0.020 Unstable angina 19.8% 17.8% STEMI 36.6% 39.2% NSTEMI 41.9% 41.1%

Disease history Angina pectoris 48.7% 46.8% 0.062 Asthma 2.71% 2.63% 0.86 Chronic obstructive pulmonary disease 5.37% 5.97% 0.23 Chronic renal disease 3.77% 3.60% 0.71 Diabetes mellitus 23.2% 22.9% 0.79 Dyslipidemia including hypercholesterolemia 45.5% 45.3% 0.82 Dyspnea 14.7% 15.7% 0.16 Gout 2.66% 2.52% 0.71 Hypertension 64.8% 66.8% 0.041 Myocardial infarction 21.0% 20.3% 0.40 Peripheral arterial disease 7.16% 6.40% 0.15 Stroke 3.64% 4.10% 0.27

5

Congestive heart failure 6.38% 6.37% 1.00 Transient ischemic attack 2.49% 2.52% 0.97 Revascularisation prior CABG 5.67% 5.47% 0.69 Revascularisation prior PCI 12.2% 11.6% 0.41

Medications ACE Inhibitors on day of randomization 58.3% 56.9% 0.15 Angiotensin II receptor on day of randomization 8.06% 8.14% 0.92 ASA on day of randomization 96.4% 96.2% 0.67 Beta blockers on day of rand 78.6% 76.4% 0.010 Calcium channel blocker on day of randomization 14.9% 15.1% 0.78 Glycoprotein IIb/IIIa inhibitor during index hosp. 22.1% 23.0% 0.28 Heparin during index hospitalization 61.4% 64.8% 0.00059 Lipid lowering agent on day of randomization 80.2% 79.3% 0.27

Outcomes CV death 3.79% 3.13% 0.086 Dyspnea 13.3% 11.3% 0.0035 Major bleeding 10.3% 9.47% 0.19 Myocardial infarction 6.58% 5.40% 0.016 Non CABG related major bleeding 3.67% 3.02% 0.085 Non CABG related major or minor bleeding 7.26% 6.40% 0.10 Primary composite endpoint 10.3% 8.49% 0.0022 Stroke 1.28% 1.03% 0.30

6

Table S5. Clinical variables and IL-‐18 levels in the discovery and replication cohort. Two-‐sample Wilcoxon test was used to calculate P-‐values. Discovery Replication

Trait P Min 1st Qu.* Median Mean

3rd Qu. Max Min 1st Qu. Median Mean

3rd Qu. Max

Age (years) 0.043 20 55 63 62.8 71 91 20 54 62 62.4 71 95 Body mass index (kg/m2) 0.25 14 25 28 28.1 31 56 14 25 28 28.2 31 70

Interleukin 18 (pg/mL) 0.00042 12.5 178 230 261 301 12100 41 181 238 269 316 6765 Qu. -‐ quartile

7

Table S6. Genome-‐wide significant SNPs in the discovery cohort and the replication analyses

Discovery cohort Replication cohort SNP name Chr Position Allele* N Beta SE beta P1df SNP name MAF HWE† Info N Beta SE beta P kgp1626348 2 32484955 G 3749 -‐0.111 0.010 6.3E-‐31 Not Available

kgp6958734 2 32489851 G 3770 -‐0.111 0.010 3.4E-‐30 rs385076 0.385 0.43 0.97 5563 -‐0.113 0.008 3.5E-‐42 kgp12219831 2 32271364 G 3776 -‐0.109 0.010 3.9E-‐30 rs67157050 0.427 0.35 0.99 5563 -‐0.104 0.008 1.9E-‐37 kgp10964192 2 32460934 G 3774 -‐0.109 0.010 6.3E-‐30 rs212716 0.424 0.35 1.00 5563 -‐0.105 0.008 2.3E-‐38 rs7577696 2 32278782 A 3778 -‐0.108 0.010 2.8E-‐29 rs7577696 0.427 0.40 1.00 5563 -‐0.102 0.008 9.2E-‐37 rs3769604 2 32322495 G 3778 -‐0.108 0.010 3.0E-‐29 rs3769604 0.427 0.40 1.00 5563 -‐0.104 0.008 6.4E-‐38 rs7581340 2 32337391 G 3772 -‐0.108 0.010 3.8E-‐29 rs7581340 0.425 0.37 1.00 5563 -‐0.105 0.008 1.2E-‐38 kgp7625774 2 32265917 C 3778 -‐0.104 0.010 8.8E-‐27 rs11124274 0.400 0.35 0.97 5563 -‐0.105 0.008 1.9E-‐36 rs455060 2 32475109 A 3774 -‐0.102 0.010 1.6E-‐26 rs455060 0.410 0.78 1.00 5563 -‐0.090 0.008 1.4E-‐28 rs3769602 2 32381829 G 3770 -‐0.104 0.010 2.8E-‐26 rs3769602 0.377 0.14 1.00 5563 -‐0.093 0.008 6.0E-‐29 rs12614686 2 32363171 A 3775 -‐0.103 0.010 4.2E-‐26 rs12614686 0.375 0.12 1.00 5563 -‐0.092 0.008 4.7E-‐28 kgp1283730 2 32279988 G 3769 -‐0.102 0.010 9.5E-‐26 rs78902123 0.413 0.68 1.00 5563 -‐0.098 0.008 1.5E-‐33 kgp672639 2 32262201 A 3767 -‐0.101 0.010 3.1E-‐25 rs6748621 0.415 0.45 0.99 5563 -‐0.098 0.008 2.9E-‐33 kgp2090984 2 32300569 G 3778 -‐0.100 0.010 3.3E-‐25 rs12992743 0.404 0.51 0.98 5563 -‐0.099 0.008 1.0E-‐33 rs2365555 2 32280699 A 3774 -‐0.099 0.010 1.5E-‐24 rs2365555 0.413 0.70 1.00 5563 -‐0.098 0.008 1.2E-‐33 rs5744256 11 112022848 A 3773 -‐0.114 0.011 9.4E-‐24 rs5744256 0.230 2.11 1.00 5563 -‐0.101 0.009 1.2E-‐26 kgp10655020 11 112049140 A 3769 -‐0.114 0.011 1.1E-‐23 rs12796114 0.237 1.82 0.99 5563 -‐0.101 0.009 1.4E-‐26 kgp11603113 11 112025915 A 3746 -‐0.114 0.011 2.6E-‐23 rs4988359 0.230 2.11 1.00 5563 -‐0.101 0.009 1.5E-‐26 rs212701 2 32444054 G 3773 -‐0.096 0.010 4.7E-‐23 rs212701 0.395 0.32 1.00 5563 -‐0.090 0.008 4.3E-‐28 kgp5339449 2 32435176 G 3777 0.093 0.009 9.8E-‐23 rs212687 0.491 0.13 1.00 5563 0.089 0.008 3.2E-‐28 rs2268796 2 31782280 G 3776 -‐0.094 0.010 9.9E-‐23 rs2268796 0.432 0.77 1.00 5563 -‐0.088 0.008 8.0E-‐28 kgp50884 2 31868877 G 3775 -‐0.094 0.010 1.4E-‐22 rs693918 0.431 0.65 1.00 5563 -‐0.088 0.008 1.6E-‐27 rs12991444 2 32265125 C 3778 -‐0.099 0.010 5.0E-‐22 rs12991444 0.308 0.40 1.00 5563 -‐0.096 0.009 1.4E-‐28 kgp414078 2 31833561 G 3710 -‐0.093 0.010 1.5E-‐21 rs610758 0.442 0.44 0.99 5563 -‐0.084 0.008 1.3E-‐25 rs410469 2 32476992 C 3768 -‐0.098 0.010 1.7E-‐21 rs410469 0.308 0.35 1.00 5563 -‐0.099 0.009 3.2E-‐30 kgp1349080 2 32398110 A 3778 0.091 0.010 1.7E-‐21 rs13427170 0.480 0.12 1.00 5563 0.087 0.008 3.2E-‐27 rs7562653 2 32478629 G 3778 -‐0.097 0.010 2.8E-‐21 rs7562653 0.306 0.31 1.00 5563 -‐0.101 0.009 4.8E-‐31 rs11691939 2 32339561 G 3772 -‐0.097 0.010 4.2E-‐21 rs11691939 0.307 0.26 1.00 5563 -‐0.098 0.009 2.7E-‐29

8

rs34197800 2 32389646 C 3775 -‐0.097 0.010 5.5E-‐21 rs34197800 0.307 0.31 1.00 5563 -‐0.098 0.009 2.5E-‐29 rs212761 2 32429288 G 3752 -‐0.094 0.010 7.2E-‐20 rs212761 0.307 0.25 1.00 5563 -‐0.098 0.009 5.4E-‐29 kgp2349770 2 32101059 A 3778 0.087 0.010 1.9E-‐19 rs1272585 0.492 0.12 0.99 5563 0.077 0.008 1.4E-‐21 rs4952220 2 31765556 A 3769 -‐0.086 0.010 2.1E-‐19 rs4952220 0.438 1.01 1.00 5563 -‐0.084 0.008 2.7E-‐25 rs7581432 2 32395315 G 3777 0.086 0.010 2.3E-‐19 rs7581432 0.498 0.02 1.00 5563 0.083 0.008 9.8E-‐25 rs10208246 2 32386659 G 3775 0.086 0.010 2.7E-‐19 rs10208246 0.467 0.09 1.00 5563 0.084 0.008 3.7E-‐25 rs467523 2 32301631 A 3771 0.086 0.010 2.7E-‐19 rs467523 0.468 0.08 1.00 5563 0.083 0.008 7.0E-‐25 kgp6290309 2 32345563 A 3777 0.086 0.010 3.3E-‐19 rs56208031 0.469 0.14 1.00 5563 0.083 0.008 1.2E-‐24 rs806584 2 31912164 A 3768 0.086 0.010 3.9E-‐19 rs806584 0.492 0.44 1.00 5563 0.074 0.008 4.6E-‐20 rs806645 2 31807940 G 3776 -‐0.089 0.010 6.0E-‐19 rs806645 0.329 0.49 1.00 5563 -‐0.083 0.009 4.3E-‐22 kgp11852778 2 32019747 A 3778 0.085 0.010 6.8E-‐19 rs223665 0.488 0.12 1.00 5563 0.075 0.008 1.9E-‐20 rs212736 2 32473126 G 3764 -‐0.094 0.011 1.2E-‐18 rs212736 0.273 0.59 1.00 5563 -‐0.082 0.009 1.1E-‐19 rs13013695 2 32391231 G 3770 -‐0.092 0.010 1.4E-‐18 rs13013695 0.285 1.54 1.00 5563 -‐0.084 0.009 1.6E-‐21 kgp2146923 2 32385898 C 3769 -‐0.084 0.010 1.5E-‐18 Not Available

rs2754530 2 31803403 G 3763 -‐0.088 0.010 1.7E-‐18 rs2754530 0.330 0.47 1.00 5563 -‐0.084 0.009 6.6E-‐23 rs223631 2 31986063 G 3771 0.084 0.010 1.7E-‐18 rs223631 0.489 0.26 1.00 5563 0.069 0.008 8.5E-‐18 kgp4746395 2 32424019 C 3778 0.083 0.010 2.1E-‐18 rs212755 0.496 0.09 1.00 5563 0.083 0.008 8.1E-‐25 rs12470143 2 31763558 G 3775 0.084 0.010 2.5E-‐18 rs12470143 0.470 0.06 1.00 5563 0.076 0.008 5.2E-‐21 kgp4484115 2 32438655 G 3772 -‐0.090 0.010 6.1E-‐18 rs462878 0.295 0.69 1.00 5563 -‐0.082 0.009 9.4E-‐21 rs212689 2 32437338 A 3763 -‐0.089 0.010 1.0E-‐17 rs212689 0.295 0.69 1.00 5563 -‐0.082 0.009 1.2E-‐20 kgp719690 2 31928899 G 3777 -‐0.090 0.011 1.4E-‐17 rs1510917 0.298 1.25 0.97 5563 -‐0.084 0.009 6.4E-‐21 kgp10595315 2 32381109 C 3772 0.083 0.010 1.4E-‐17 rs6709048 0.377 0.21 0.89 5563 0.078 0.009 1.0E-‐18 kgp587321 2 31695655 G 3778 -‐0.081 0.010 1.6E-‐17 exm2265132 0.429 1.01 1.00 5563 -‐0.073 0.008 2.3E-‐19 kgp4139677 2 32182528 A 3770 0.083 0.010 2.5E-‐17 rs62142080 0.402 0.88 0.99 5563 0.077 0.008 9.5E-‐21 kgp5359028 2 31922672 G 3769 -‐0.088 0.011 5.1E-‐17 rs6748639 0.298 1.23 0.97 5563 -‐0.084 0.009 6.4E-‐21 kgp12097157 2 32325414 G 3758 -‐0.087 0.010 6.5E-‐17 rs34835885 0.288 0.73 0.97 5563 -‐0.084 0.009 5.6E-‐21 rs177083 2 32447718 A 3772 -‐0.079 0.009 1.1E-‐16 rs177083 0.478 0.03 1.00 5563 -‐0.073 0.008 2.4E-‐19 rs12467911 2 31782791 G 3776 -‐0.085 0.010 1.2E-‐16 rs12467911 0.307 0.54 1.00 5563 -‐0.080 0.009 3.9E-‐20 rs11695295 2 31973127 A 3771 -‐0.083 0.010 1.6E-‐16 rs11695295 0.335 0.76 1.00 5563 -‐0.078 0.009 5.4E-‐20 rs682895 2 31871583 C 3778 -‐0.084 0.010 1.7E-‐16 rs682895 0.309 0.30 1.00 5563 -‐0.081 0.009 1.8E-‐20

9

rs212704 2 32450348 A 3778 -‐0.078 0.009 2.4E-‐16 rs212704 0.478 0.03 1.00 5563 -‐0.073 0.008 2.1E-‐19 kgp4015691 2 32096589 A 3771 -‐0.082 0.010 3.4E-‐16 Not Available

rs522638 2 31805675 G 3776 -‐0.083 0.010 6.4E-‐16 rs522638 0.316 0.49 1.00 5563 -‐0.080 0.009 3.3E-‐20 rs553464 2 31873476 A 3775 -‐0.078 0.010 8.8E-‐16 rs553464 0.376 0.24 1.00 5563 -‐0.077 0.008 1.7E-‐20 rs11904162 2 32070489 A 3774 -‐0.079 0.010 2.1E-‐15 rs11904162 0.342 0.71 1.00 5563 -‐0.077 0.009 1.7E-‐19 kgp613301 2 31757727 A 3774 -‐0.081 0.010 2.5E-‐15 Not Available

rs2250417 11 112085316 G 3773 0.075 0.009 2.5E-‐15 rs2250417 0.475 2.50 1.00 5563 0.085 0.008 7.4E-‐26 rs206811 2 31636915 G 3771 -‐0.077 0.010 4.4E-‐15 rs206811 0.370 1.45 1.00 5563 -‐0.068 0.008 2.5E-‐16 kgp153485 11 112110091 A 3774 -‐0.084 0.011 5.6E-‐15 rs35082717 0.275 1.35 0.96 5563 -‐0.078 0.009 3.3E-‐17 rs206816 2 31644983 G 3776 -‐0.074 0.010 1.5E-‐14 rs206816 0.399 0.67 1.00 5563 -‐0.064 0.008 4.8E-‐15 rs160804 2 32057759 G 3776 0.077 0.010 1.6E-‐14 rs160804 0.366 1.52 1.00 5563 0.067 0.008 9.1E-‐16 rs7575607 2 31640455 A 3761 -‐0.074 0.010 1.9E-‐14 rs7575607 0.401 2.39 1.00 5563 -‐0.071 0.008 2.5E-‐18 kgp2068785 2 32424288 G 3765 -‐0.073 0.010 2.3E-‐14 rs212756 0.453 0.21 0.97 5563 -‐0.072 0.008 3.6E-‐18 rs4952203 2 32103689 G 3773 -‐0.083 0.011 3.3E-‐14 rs4952203 0.258 2.12 1.00 5563 -‐0.074 0.009 5.0E-‐16 rs6752375 2 32247942 G 3776 0.078 0.010 3.7E-‐14 rs6752375 0.309 0.38 1.00 5563 0.069 0.009 2.7E-‐15 rs623419 2 31834078 G 3773 -‐0.076 0.010 8.9E-‐14 rs623419 0.329 6.3E-‐16 1.00 5563 -‐0.075 0.009 2.8E-‐18 kgp1925342 2 31697681 G 3724 -‐0.073 0.010 9.7E-‐14 rs58967340 0.415 1.34 1.00 5563 -‐0.069 0.008 4.1E-‐17 kgp10204526 11 112049862 A 3777 0.074 0.010 1.2E-‐13 Not Available

rs2064813 2 32212935 A 3772 -‐0.087 0.012 1.7E-‐13 rs2064813 0.200 0.71 1.00 5563 -‐0.069 0.010 1.0E-‐11 kgp6121370 2 31741566 G 3774 -‐0.077 0.010 2.0E-‐13 rs56175176 0.294 0.89 1.00 5563 -‐0.070 0.009 2.7E-‐15 rs2224310 2 31742467 A 3774 -‐0.076 0.010 2.3E-‐13 rs2224310 0.295 0.97 1.00 5563 -‐0.070 0.009 2.0E-‐15 kgp11986083 2 31733657 C 3767 0.071 0.010 3.2E-‐13 rs56406022 0.421 0.28 0.99 5563 0.056 0.008 8.4E-‐12 rs3754835 2 32206029 C 3775 -‐0.070 0.010 4.8E-‐13 rs3754835 0.398 0.12 1.00 5563 -‐0.068 0.008 3.8E-‐16 kgp10864446 2 31730255 G 3772 0.069 0.010 4.8E-‐13 rs72794621 0.440 0.35 1.00 5563 0.061 0.008 8.6E-‐14 rs612224 2 31811870 A 3775 -‐0.074 0.010 4.9E-‐13 rs612224 0.313 0.64 1.00 5563 -‐0.067 0.009 1.6E-‐14 rs6739055 2 32071502 A 3726 -‐0.075 0.010 5.4E-‐13 rs6739055 0.307 0.76 1.00 5563 -‐0.070 0.009 1.2E-‐15 rs2365778 2 31738219 A 3773 0.067 0.010 1.6E-‐12 rs2365778 0.487 0.79 1.00 5563 0.060 0.008 6.2E-‐14 rs766273 2 31670523 A 3776 0.067 0.009 1.8E-‐12 rs766273 0.462 0.41 1.00 5563 0.060 0.008 1.1E-‐13 kgp3194900 11 112072930 G 3769 0.070 0.010 3.3E-‐12 rs4935984 0.339 1.88 0.97 5563 0.074 0.009 4.7E-‐18 kgp11899968 2 31859226 A 3770 -‐0.073 0.010 3.4E-‐12 Not Available

10

* Effective allele † -‐log10(HWE P-‐value)

kgp11253834 2 31705611 G 3776 0.065 0.009 6.2E-‐12 rs4952263 0.460 0.46 0.99 5563 0.060 0.008 9.5E-‐14 kgp41024 2 31619559 G 3778 -‐0.067 0.010 7.9E-‐12 rs206859 0.363 1.96 0.99 5563 -‐0.064 0.008 2.2E-‐14 rs206827 2 31686309 G 3773 -‐0.068 0.010 1.1E-‐11 rs206827 0.364 0.60 1.00 5563 -‐0.062 0.008 1.1E-‐13 kgp4220849 2 31695729 C 3778 0.064 0.010 1.3E-‐11 rs1033689 0.451 0.38 1.00 5563 0.061 0.008 7.9E-‐14 kgp4855063 2 31663803 G 3773 0.064 0.010 2.5E-‐11 rs17545483 0.451 0.38 1.00 5563 0.059 0.008 3.5E-‐13 kgp11764327 2 31866595 G 3742 0.069 0.010 2.7E-‐11 rs55679051 0.339 0.45 0.95 5563 0.066 0.009 2.9E-‐14 rs761925 2 31693451 G 3775 0.063 0.009 3.3E-‐11 rs761925 0.449 0.46 1.00 5563 0.060 0.008 9.9E-‐14 rs185925 2 31609993 A 3766 -‐0.065 0.010 5.0E-‐11 rs185925 0.339 1.95 1.00 5563 -‐0.067 0.008 2.7E-‐15 kgp10627621 2 31867905 G 3775 0.068 0.011 9.7E-‐11 rs635304 0.317 0.94 0.94 5563 0.067 0.009 6.3E-‐14 kgp10361856 11 112016514 G 3778 0.065 0.010 1.8E-‐10 rs5744280 0.337 1.85 0.99 5563 0.076 0.009 9.1E-‐19 rs2300697 2 31786637 A 3772 -‐0.061 0.010 1.8E-‐10 rs2300697 0.429 0.28 1.00 5563 -‐0.058 0.008 1.4E-‐12 rs206826 2 31683940 A 3756 -‐0.065 0.010 2.8E-‐10 rs206826 0.309 0.76 1.00 5563 -‐0.059 0.009 1.6E-‐11 rs206847 2 31611367 G 3778 -‐0.062 0.010 3.1E-‐10 rs206847 0.354 1.96 1.00 5563 -‐0.064 0.008 2.0E-‐14 kgp5900834 2 31788989 A 3775 -‐0.059 0.010 6.2E-‐10 rs2208532 0.440 0.32 0.99 5563 -‐0.057 0.008 3.7E-‐12 kgp1805846 11 111994216 G 3778 -‐0.080 0.013 8.1E-‐10 rs77203424 0.173 0.21 0.88 5563 -‐0.104 0.011 1.3E-‐19 rs2073316 2 31611029 G 3778 0.058 0.010 1.4E-‐09 rs2073316 0.471 0.69 1.00 5563 0.054 0.008 1.2E-‐11 rs7595578 2 31656380 G 3737 0.057 0.010 1.9E-‐09 rs7595578 0.456 0.35 1.00 5563 0.056 0.008 4.3E-‐12 kgp6152773 2 31626385 A 3777 0.057 0.010 3.8E-‐09 rs1429372 0.444 0.60 0.97 5563 0.054 0.008 6.0E-‐11 rs438408 2 32495395 A 3774 -‐0.055 0.010 1.8E-‐08 rs438408 0.387 0.45 1.00 5563 -‐0.057 0.008 8.0E-‐12 kgp8095374 2 31657292 G 3766 0.053 0.009 2.3E-‐08 rs11674100 0.477 0.33 1.00 5563 0.053 0.008 7.5E-‐11 kgp4440629 8 144650503 G 3774 -‐0.052 0.009 3.1E-‐08 rs13271361 0.461 0.03 0.97 5563 -‐0.048 0.008 6.0E-‐09

11

Table S7. Genome-‐wide significant SNPs in the pooled data (discovery + replication cohort) Chr P/C* SNP Allele† MAF HWE‡ Info N Position Beta SE beta P 2 P rs385076 T 0.39 0.95 0.98 9340 32489851 0.113 0.006 7.0E-‐72 2 P chr2:32480606:D D 0.42 1.34 0.98 9340 32480606 0.108 0.006 2.8E-‐68 2 P chr2:32481793:D D 0.42 0.84 1.00 9340 32481793 0.107 0.006 3.1E-‐68 2 P chr2:32481795 T 0.42 0.85 1.00 9340 32481795 0.107 0.006 3.2E-‐68 2 P rs435572 A 0.43 0.66 0.97 9340 32488081 0.108 0.006 3.5E-‐68 2 P rs479333 C 0.41 0.85 0.98 9340 32489158 0.109 0.006 5.7E-‐68 2 P chr2:32480607:D D 0.41 1.12 0.98 9340 32480607 0.108 0.006 6.2E-‐68 2 P rs408813 T 0.42 0.85 1.00 9340 32476390 0.107 0.006 8.9E-‐68 2 P rs428002 G 0.43 0.75 0.99 9340 32487774 0.107 0.006 1.3E-‐67 2 P rs466125 G 0.43 0.69 0.99 9340 32462092 0.107 0.006 1.3E-‐67 2 P rs2566483 G 0.42 0.77 1.00 9340 32484467 0.107 0.006 1.3E-‐67 2 P rs7577408 T 0.43 0.92 0.99 9340 32306113 -‐0.107 0.006 1.3E-‐67 2 P rs659239 T 0.43 0.77 1.00 9340 32484569 0.107 0.006 2.1E-‐67 2 P chr2:32484952:D D 0.43 0.78 0.99 9340 32484952 0.107 0.006 3.4E-‐67 2 P rs1265341 C 0.43 0.70 0.97 9340 32488060 0.108 0.006 3.9E-‐67 2 P rs212715 C 0.42 0.82 1.00 9340 32460886 0.106 0.006 4.0E-‐67 2 P rs212717 G 0.42 0.80 1.00 9340 32461640 0.106 0.006 4.3E-‐67 2 P rs212716 A 0.42 0.80 1.00 9340 32460934 0.106 0.006 5.4E-‐67 2 P rs443609 C 0.43 0.87 1.00 9340 32483593 0.106 0.006 6.0E-‐67 2 P rs7559964 G 0.42 0.71 0.99 9340 32333866 -‐0.107 0.006 9.5E-‐67 2 P rs36014814 G 0.42 0.77 0.99 9340 32304959 -‐0.106 0.006 1.4E-‐66 2 P rs7600885 T 0.42 0.79 0.99 9340 32272254 -‐0.106 0.006 1.7E-‐66 2 P rs7581340 T 0.42 0.72 1.00 9340 32337391 -‐0.106 0.006 3.2E-‐66 2 P rs1265340 T 0.41 1.24 0.97 9340 32486917 0.107 0.006 3.3E-‐66 2 P rs7601267 A 0.43 0.64 0.99 9340 32272399 -‐0.106 0.006 3.7E-‐66 2 P rs67157050 T 0.43 0.57 0.99 9340 32271364 -‐0.106 0.006 4.9E-‐66

12

2 P rs34856365 G 0.42 0.80 1.00 9340 32305000 -‐0.105 0.006 5.0E-‐66 2 P rs4952248 A 0.42 0.54 0.99 9340 32343669 -‐0.106 0.006 5.3E-‐66 2 P rs6543647 G 0.43 0.60 0.99 9340 32271742 -‐0.106 0.006 5.9E-‐66 2 P rs7604559 T 0.43 0.71 0.99 9340 32273202 -‐0.106 0.006 6.8E-‐66 2 P rs6749336 A 0.43 0.64 0.99 9340 32271710 -‐0.106 0.006 7.2E-‐66 2 P rs2365558 T 0.42 0.64 1.00 9340 32336657 -‐0.106 0.006 7.5E-‐66 2 P rs72862234 A 0.43 0.60 0.99 9340 32270146 -‐0.106 0.006 7.6E-‐66 2 P rs2235134 A 0.43 0.64 1.00 9340 32332543 -‐0.105 0.006 7.9E-‐66 2 P rs212718 C 0.43 0.80 0.99 9340 32461833 0.105 0.006 7.9E-‐66 2 P rs7573543 T 0.43 0.63 1.00 9340 32342508 -‐0.105 0.006 8.2E-‐66 2 P rs6760105 G 0.42 0.79 1.00 9340 32307386 -‐0.105 0.006 8.3E-‐66 2 P rs7586448 G 0.43 0.46 0.99 9340 32268640 -‐0.106 0.006 8.5E-‐66 2 P rs4952250 G 0.42 0.57 0.99 9340 32343699 -‐0.106 0.006 8.5E-‐66 2 P rs17767988 A 0.42 0.74 1.00 9340 32286826 -‐0.105 0.006 8.7E-‐66 2 P rs11686061 C 0.43 0.78 1.00 9340 32321394 -‐0.105 0.006 9.0E-‐66 2 P rs10490360 G 0.42 0.80 1.00 9340 32296268 -‐0.105 0.006 9.3E-‐66 2 P rs212739 A 0.42 0.80 1.00 9340 32404703 0.105 0.006 9.3E-‐66 2 P rs3769604 A 0.43 0.75 1.00 9340 32322495 -‐0.105 0.006 9.3E-‐66 2 P rs12617289 G 0.43 0.63 1.00 9340 32341399 -‐0.105 0.006 9.6E-‐66 2 P rs212679 C 0.43 0.87 1.00 9340 32431107 0.105 0.006 9.9E-‐66 2 P rs7575139 C 0.42 0.80 1.00 9340 32291334 -‐0.105 0.006 1.1E-‐65 2 P rs7566162 C 0.43 0.74 1.00 9340 32324072 -‐0.105 0.006 1.1E-‐65 2 P rs11124276 G 0.43 0.72 1.00 9340 32318428 -‐0.105 0.006 1.1E-‐65 2 P rs13029752 G 0.42 0.75 1.00 9340 32293554 -‐0.105 0.006 1.1E-‐65 2 P rs11681731 T 0.43 0.66 1.00 9340 32345325 -‐0.105 0.006 1.1E-‐65 2 P rs7605242 A 0.43 0.75 1.00 9340 32324135 -‐0.105 0.006 1.2E-‐65 2 P rs2280967 C 0.42 0.80 1.00 9340 32289746 -‐0.105 0.006 1.2E-‐65 2 P rs11124277 G 0.43 0.74 1.00 9340 32320370 -‐0.105 0.006 1.3E-‐65

13

2 P rs7600173 C 0.43 0.50 0.99 9340 32268410 -‐0.105 0.006 1.5E-‐65 2 P rs12989936 C 0.43 0.50 0.99 9340 32268586 -‐0.105 0.006 1.5E-‐65 2 P rs7561519 C 0.43 0.72 1.00 9340 32312700 -‐0.105 0.006 1.5E-‐65 2 P rs6747488 T 0.43 0.74 1.00 9340 32311284 -‐0.105 0.006 1.6E-‐65 2 P rs4952247 C 0.42 0.69 0.99 9340 32338915 -‐0.106 0.006 2.5E-‐65 2 P rs212760 A 0.43 0.79 1.00 9340 32429222 0.105 0.006 2.6E-‐65 2 P rs6543649 G 0.42 0.69 0.99 9340 32339040 -‐0.105 0.006 2.7E-‐65 2 P rs56740303 A 0.42 0.75 1.00 9340 32304656 -‐0.105 0.006 3.0E-‐65 2 P rs7581032 G 0.42 0.66 1.00 9340 32337166 -‐0.105 0.006 3.1E-‐65 2 P rs7370704 G 0.43 0.55 0.99 9340 32257717 -‐0.105 0.006 3.7E-‐65 2 P rs12620922 A 0.42 0.79 0.99 9340 32308102 -‐0.105 0.006 4.2E-‐65 2 P rs13022197 A 0.42 0.66 0.99 9340 32343167 -‐0.105 0.006 4.3E-‐65 2 P rs7608127 G 0.42 0.72 1.00 9340 32279923 -‐0.105 0.006 4.6E-‐65 2 P rs6737500 T 0.43 0.58 0.99 9340 32263087 -‐0.105 0.006 4.8E-‐65 2 P rs13000753 C 0.42 0.71 1.00 9340 32282297 -‐0.105 0.006 6.0E-‐65 2 P rs13024004 G 0.42 0.71 1.00 9340 32282362 -‐0.105 0.006 6.2E-‐65 2 P rs212678 G 0.43 0.85 0.99 9340 32430894 0.105 0.006 9.1E-‐65 2 P chr2:32298150:I D 0.43 0.89 0.99 9340 32298150 -‐0.105 0.006 1.0E-‐64 2 P chr2:32304694:I D 0.41 0.68 0.97 9340 32304694 -‐0.106 0.006 1.1E-‐64 2 P rs7577696 G 0.43 0.69 1.00 9340 32278782 -‐0.104 0.006 1.5E-‐64 2 P rs35650265 G 0.42 0.65 0.99 9340 32275311 -‐0.105 0.006 3.2E-‐64 2 P rs11691879 A 0.41 0.68 0.98 9340 32274217 -‐0.106 0.006 5.1E-‐64 2 P rs212745 C 0.42 0.96 1.00 9340 32412832 0.104 0.006 8.1E-‐64 2 P rs13017189 G 0.42 0.98 1.00 9340 32281280 -‐0.103 0.006 2.1E-‐63 2 P rs212746 T 0.42 0.52 1.00 9340 32413067 0.103 0.006 3.8E-‐63 2 P rs12617290 G 0.43 0.44 0.99 9340 32341408 -‐0.104 0.006 7.2E-‐63 2 P rs115985725 A 0.41 0.68 0.97 9340 32335807 -‐0.105 0.006 9.3E-‐63 2 P rs9677104 T 0.40 0.53 0.97 9340 32335099 -‐0.106 0.006 1.0E-‐62

14

2 P chr2:32314464:I D 0.40 0.53 0.93 9340 32314464 -‐0.107 0.006 2.4E-‐62 2 P rs3769606 C 0.40 0.47 0.98 9340 32317550 -‐0.105 0.006 3.5E-‐62 2 P rs6725184 T 0.40 0.45 0.98 9340 32330885 -‐0.104 0.006 4.7E-‐62 2 P rs11124274 A 0.40 0.41 0.98 9340 32265917 -‐0.104 0.006 7.1E-‐62 2 P rs11676938 C 0.40 0.53 0.98 9340 32316023 -‐0.104 0.006 4.2E-‐61 2 P rs78733036 C 0.39 0.34 0.96 9340 32326352 -‐0.105 0.006 1.1E-‐60 2 P rs652978 T 0.44 0.73 0.98 9340 32286411 -‐0.102 0.006 1.8E-‐60 2 P rs62134033 A 0.40 1.06 0.99 9340 32479967 0.102 0.006 1.4E-‐59 2 P chr2:32479421:I T 0.41 1.53 0.97 9340 32479421 0.102 0.006 1.6E-‐59 2 P rs374743 G 0.42 0.50 0.89 9340 32494190 0.106 0.007 3.2E-‐59 2 P rs6758024 C 0.42 0.71 1.00 9340 32294486 -‐0.100 0.006 4.1E-‐59 2 P rs141443443 T 0.38 0.47 0.96 9340 32326237 -‐0.104 0.006 5.5E-‐59 2 P rs466126 G 0.42 0.81 0.99 9340 32462094 0.101 0.006 5.5E-‐59 2 P rs6738349 C 0.42 0.73 0.99 9340 32314131 -‐0.100 0.006 1.1E-‐58 2 P chr2:32305497:I D 0.41 0.80 1.00 9340 32305497 -‐0.099 0.006 3.9E-‐58 2 P chr2:32305669:I D 0.41 0.80 1.00 9340 32305669 -‐0.099 0.006 3.9E-‐58 2 P rs2280969 A 0.41 0.90 1.00 9340 32290147 -‐0.099 0.006 7.2E-‐58 2 P rs12474443 T 0.41 0.70 1.00 9340 32337872 -‐0.099 0.006 8.4E-‐58 2 P rs12992743 A 0.41 0.67 0.99 9340 32300569 -‐0.100 0.006 1.1E-‐57 2 P rs78902123 T 0.41 0.68 1.00 9340 32279988 -‐0.099 0.006 1.2E-‐57 2 P rs11124275 A 0.41 0.75 1.00 9340 32303762 -‐0.099 0.006 1.4E-‐57 2 P rs11683931 A 0.41 0.75 1.00 9340 32304068 -‐0.099 0.006 1.5E-‐57 2 P rs4952249 T 0.41 0.55 0.99 9340 32343673 -‐0.100 0.006 1.6E-‐57 2 P rs6748621 C 0.41 0.45 1.00 9340 32262201 -‐0.099 0.006 3.7E-‐57 2 P rs212680 C 0.45 0.44 0.94 9340 32431407 0.101 0.006 3.8E-‐57 2 P chr2:32325025:I D 0.37 0.41 0.91 9340 32325025 -‐0.105 0.007 6.1E-‐57 2 P rs2365555 C 0.41 0.75 1.00 9340 32280699 -‐0.098 0.006 6.4E-‐57 2 P chr2:32295136:D A 0.41 0.13 0.92 9340 32295136 -‐0.103 0.007 6.9E-‐57

15

2 P rs469305 T 0.44 0.23 0.97 9340 32314473 -‐0.100 0.006 8.3E-‐57 2 P chr2:32313786:D A 0.41 0.80 0.98 9340 32313786 -‐0.099 0.006 1.7E-‐56 2 P rs13033833 G 0.38 0.50 0.95 9340 32303063 -‐0.102 0.006 5.0E-‐56 2 P chr2:32313785:D A 0.40 0.64 0.98 9340 32313785 -‐0.099 0.006 1.4E-‐55 2 P rs192297663 A 0.34 0.27 0.87 9340 32335981 -‐0.108 0.007 5.3E-‐55 2 P chr2:32355412:D A 0.37 0.52 0.99 9340 32355412 -‐0.098 0.006 7.4E-‐54 2 P rs494569 A 0.41 1.31 0.99 9340 32469622 0.096 0.006 8.1E-‐54 2 P chr2:32370724:I D 0.38 0.49 1.00 9340 32370724 -‐0.097 0.006 1.4E-‐53 2 P chr2:32466854:D D 0.41 1.07 0.99 9340 32466854 0.096 0.006 1.6E-‐53 2 P rs455060 G 0.41 1.26 1.00 9340 32475109 0.095 0.006 1.9E-‐53 2 P rs212737 T 0.41 1.24 1.00 9340 32474291 0.095 0.006 1.9E-‐53 2 P rs34976640 T 0.37 0.53 0.99 9340 32373514 -‐0.098 0.006 2.5E-‐53 2 P rs212735 C 0.41 1.24 1.00 9340 32473088 0.095 0.006 3.1E-‐53 2 P rs212731 G 0.41 1.29 1.00 9340 32472150 0.095 0.006 4.1E-‐53 2 P rs212722 G 0.42 1.44 0.98 9340 32466607 0.095 0.006 4.2E-‐53 2 P rs144736172 A 0.43 0.97 0.99 9340 31968142 0.095 0.006 4.4E-‐53 2 P rs212725 G 0.41 1.24 1.00 9340 32468602 0.095 0.006 5.0E-‐53 2 P rs212730 G 0.41 1.26 1.00 9340 32471673 0.095 0.006 5.1E-‐53 2 P rs212728 G 0.41 1.29 1.00 9340 32470307 0.095 0.006 5.3E-‐53 2 P rs212724 A 0.41 1.26 1.00 9340 32467489 0.095 0.006 5.6E-‐53 2 P rs212727 C 0.41 1.28 1.00 9340 32469728 0.095 0.006 6.0E-‐53 2 P rs212726 T 0.41 1.28 1.00 9340 32469385 0.095 0.006 6.1E-‐53 2 P rs11694630 A 0.38 0.62 1.00 9340 32376201 -‐0.097 0.006 7.0E-‐53 2 P rs7572964 T 0.38 0.62 1.00 9340 32372096 -‐0.097 0.006 7.4E-‐53 2 P rs11689817 A 0.35 0.46 0.96 9340 32364241 -‐0.100 0.007 7.4E-‐53 2 P rs11678119 C 0.38 0.62 1.00 9340 32376303 -‐0.097 0.006 7.8E-‐53 2 P rs3769602 A 0.38 0.71 1.00 9340 32381829 -‐0.097 0.006 7.8E-‐53 2 P rs11683842 A 0.38 0.65 1.00 9340 32364131 -‐0.097 0.006 9.3E-‐53

16

2 P rs12611678 A 0.37 0.52 0.98 9340 32347785 -‐0.098 0.006 9.4E-‐53 2 P rs13008192 G 0.37 0.47 1.00 9340 32350427 -‐0.097 0.006 9.8E-‐53 2 P rs2294179 A 0.37 0.57 1.00 9340 32354005 -‐0.097 0.006 1.1E-‐52 2 P rs3752916 T 0.37 0.56 1.00 9340 32354558 -‐0.097 0.006 1.1E-‐52 2 P chr2:32361482:I D 0.37 0.50 0.99 9340 32361482 -‐0.097 0.006 1.1E-‐52 2 P rs6723154 A 0.38 0.67 1.00 9340 32365161 -‐0.097 0.006 1.2E-‐52 2 P rs11683110 C 0.38 0.53 1.00 9340 32349813 -‐0.097 0.006 1.2E-‐52 2 P rs3769603 T 0.37 0.57 1.00 9340 32360887 -‐0.097 0.006 1.3E-‐52 2 P rs2294176 A 0.38 0.54 1.00 9340 32353316 -‐0.097 0.006 1.3E-‐52 2 P rs3851310 T 0.37 0.68 1.00 9340 32367986 -‐0.097 0.006 1.4E-‐52 2 P rs2886393 C 0.38 0.57 0.99 9340 32371562 -‐0.096 0.006 3.2E-‐52 2 P rs212695 G 0.41 1.32 1.00 9340 32440868 0.094 0.006 4.7E-‐52 2 P rs12614686 G 0.37 0.60 1.00 9340 32363171 -‐0.096 0.006 6.5E-‐52 2 P rs7592356 T 0.38 0.56 0.99 9340 32370344 -‐0.096 0.006 9.0E-‐52 2 P rs7562653 T 0.31 0.69 1.00 9340 32478629 0.100 0.007 3.3E-‐51 2 P chr2:32362079:I D 0.36 0.58 0.97 9340 32362079 -‐0.097 0.006 7.4E-‐51 2 P rs12996943 C 0.31 0.49 0.98 9340 32373645 -‐0.100 0.007 1.7E-‐50 2 P rs212723 C 0.42 1.22 0.98 9340 32467148 0.093 0.006 1.8E-‐50 2 P rs410469 T 0.31 0.73 1.00 9340 32476992 0.099 0.007 1.8E-‐50 2 P rs17011801 T 0.31 0.68 0.99 9340 32298072 -‐0.099 0.007 2.4E-‐50 2 P rs7556942 A 0.31 0.59 1.00 9340 32295694 -‐0.099 0.007 2.7E-‐50 2 P rs7604289 A 0.37 0.67 0.98 9340 32374000 -‐0.095 0.006 2.9E-‐50 2 P rs12470196 C 0.44 0.55 1.00 9340 31763752 0.092 0.006 3.1E-‐50 2 P chr2:32463733:I C 0.40 1.66 0.97 9340 32463733 0.094 0.006 3.9E-‐50 2 P rs13006495 T 0.31 0.57 1.00 9340 32355490 -‐0.099 0.007 4.1E-‐50 2 P rs35112079 A 0.29 0.53 0.97 9340 32302079 -‐0.102 0.007 4.3E-‐50 2 P rs212703 G 0.49 0.05 1.00 9340 32446613 0.091 0.006 4.8E-‐50 2 P rs805831 C 0.31 0.67 0.99 9340 32484228 0.099 0.007 5.1E-‐50

17

2 P rs2280968 T 0.31 0.57 1.00 9340 32290040 -‐0.099 0.007 5.7E-‐50 2 P rs2300703 T 0.43 0.57 1.00 9340 31799509 0.092 0.006 5.8E-‐50 2 P rs212686 T 0.49 0.08 1.00 9340 32434869 0.091 0.006 7.6E-‐50 2 P rs212701 T 0.39 0.80 1.00 9340 32444054 0.093 0.006 7.6E-‐50 2 P rs212753 A 0.49 0.02 1.00 9340 32421355 0.091 0.006 7.8E-‐50 2 P rs212684 G 0.31 0.72 1.00 9340 32433058 0.098 0.007 8.0E-‐50 2 P chr2:32433747:D A 0.49 0.07 1.00 9340 32433747 0.091 0.006 1.1E-‐49 2 P rs6543648 A 0.31 0.62 0.99 9340 32330314 -‐0.099 0.007 1.3E-‐49 2 P rs212699 A 0.39 0.81 1.00 9340 32443519 0.092 0.006 1.4E-‐49 2 P rs212687 A 0.49 0.08 1.00 9340 32435176 0.091 0.006 1.7E-‐49 2 P rs212698 A 0.39 0.80 1.00 9340 32442997 0.092 0.006 1.7E-‐49 2 P rs12991444 T 0.31 0.51 1.00 9340 32265125 -‐0.098 0.007 1.7E-‐49 2 P rs212685 A 0.31 0.67 1.00 9340 32434701 0.098 0.007 1.8E-‐49 2 P rs2300702 C 0.43 0.72 1.00 9340 31788018 0.091 0.006 1.8E-‐49 2 P rs212754 A 0.31 0.67 1.00 9340 32421628 0.098 0.007 1.8E-‐49 2 P rs212738 A 0.49 0.00 1.00 9340 32403322 0.091 0.006 1.9E-‐49 2 P rs7588883 A 0.49 0.01 1.00 9340 32397267 -‐0.091 0.006 1.9E-‐49 2 P rs56322034 C 0.31 0.56 1.00 9340 32353013 -‐0.098 0.007 2.0E-‐49 2 P rs430759 A 0.39 0.83 1.00 9340 32447868 0.092 0.006 2.0E-‐49 2 P rs12465351 G 0.49 0.01 1.00 9340 32394905 -‐0.091 0.006 2.1E-‐49 2 P rs6717209 C 0.49 0.02 1.00 9340 32393949 -‐0.091 0.006 2.2E-‐49 2 P rs212751 T 0.31 0.66 1.00 9340 32418808 0.098 0.007 2.2E-‐49 2 P rs4952252 T 0.49 0.04 1.00 9340 32382961 -‐0.091 0.006 2.3E-‐49 2 P chr2:32297277:D A 0.33 0.12 0.88 9340 32297277 -‐0.103 0.007 2.6E-‐49 2 P rs34197800 A 0.31 0.60 1.00 9340 32389646 -‐0.098 0.007 2.8E-‐49 2 P rs518600 C 0.44 0.50 0.99 9340 31854454 0.091 0.006 3.0E-‐49 2 P rs4952209 G 0.49 0.00 1.00 9340 32386033 -‐0.090 0.006 3.2E-‐49 2 P rs7574000 C 0.31 0.51 1.00 9340 32342888 -‐0.098 0.007 3.2E-‐49

18

2 P rs11691939 T 0.31 0.51 1.00 9340 32339561 -‐0.098 0.007 3.5E-‐49 2 P rs1090855 T 0.43 0.54 0.99 9340 31850408 0.091 0.006 3.5E-‐49 2 P rs212734 A 0.39 1.70 0.99 9340 32472753 0.092 0.006 3.7E-‐49 2 P rs2268796 A 0.43 0.75 1.00 9340 31782280 0.091 0.006 3.8E-‐49 2 P rs3769605 G 0.31 0.57 1.00 9340 32322456 -‐0.098 0.007 3.8E-‐49 2 P rs142403998 A 0.35 0.02 0.90 9340 32335947 -‐0.100 0.007 4.6E-‐49 2 P rs11124278 A 0.49 0.01 1.00 9340 32398512 -‐0.090 0.006 4.7E-‐49 2 P rs212682 A 0.31 0.66 0.99 9340 32432864 0.098 0.007 4.9E-‐49 2 P rs4407291 A 0.49 0.01 1.00 9340 32384422 -‐0.090 0.006 5.3E-‐49 2 P rs375050 C 0.31 0.67 1.00 9340 32413765 0.098 0.007 5.9E-‐49 2 P rs212732 C 0.44 0.91 0.95 9340 32472417 0.093 0.006 6.7E-‐49 2 P rs212761 T 0.31 0.52 1.00 9340 32429288 0.098 0.007 6.7E-‐49 2 P rs212714 A 0.39 1.68 0.99 9340 32460348 0.092 0.006 7.4E-‐49 2 P rs2294178 C 0.31 0.52 1.00 9340 32353324 -‐0.098 0.007 7.4E-‐49 2 P rs212762 T 0.49 0.01 1.00 9340 32429497 0.090 0.006 1.0E-‐48 2 P rs693918 A 0.43 0.58 1.00 9340 31868877 0.090 0.006 1.1E-‐48 2 P rs6756085 G 0.31 0.56 1.00 9340 32336522 -‐0.098 0.007 1.1E-‐48 2 P rs35196278 C 0.31 0.69 0.99 9340 32258536 -‐0.098 0.007 1.2E-‐48 2 P rs4519572 G 0.49 0.00 1.00 9340 32384375 -‐0.090 0.006 1.3E-‐48 2 P rs212748 T 0.49 0.07 1.00 9340 32415746 0.090 0.006 1.8E-‐48 2 P rs2366547 A 0.31 0.51 1.00 9340 32251109 -‐0.097 0.007 2.4E-‐48 2 P rs186135 C 0.32 0.67 0.97 9340 32432578 0.097 0.007 2.5E-‐48 2 P rs2268797 C 0.43 0.55 1.00 9340 31783752 0.090 0.006 2.5E-‐48 2 P chr2:32397776:D D 0.49 0.01 0.99 9340 32397776 -‐0.090 0.006 3.2E-‐48 2 P rs212740 C 0.48 0.01 0.98 9340 32408194 0.090 0.006 4.4E-‐48 2 P rs212744 G 0.49 0.03 1.00 9340 32411788 0.090 0.006 5.2E-‐48 2 P rs212743 C 0.48 0.05 0.99 9340 32410194 0.090 0.006 5.3E-‐48 2 P rs4952205 G 0.33 0.13 0.87 9340 32297273 -‐0.102 0.007 6.2E-‐48

19

2 P rs660393 T 0.40 0.93 0.94 9340 32281509 -‐0.093 0.006 6.3E-‐48 2 P rs678251 A 0.49 0.04 0.99 9340 32250361 -‐0.089 0.006 1.7E-‐47 2 P rs10172468 C 0.47 0.15 0.99 9340 32432197 0.089 0.006 2.0E-‐47 2 P rs13427170 G 0.48 0.02 1.00 9340 32398110 0.089 0.006 2.1E-‐47 2 P rs212741 A 0.48 0.02 0.99 9340 32408572 0.089 0.006 2.4E-‐47 2 P rs7557034 A 0.28 0.18 0.96 9340 32316910 -‐0.101 0.007 3.3E-‐47 2 P rs12465124 G 0.48 0.03 1.00 9340 32336679 0.089 0.006 5.1E-‐47 2 P rs13010405 T 0.28 0.12 0.97 9340 32338204 -‐0.100 0.007 5.7E-‐47 2 P rs71446036 A 0.30 0.45 0.98 9340 32226986 -‐0.097 0.007 1.0E-‐46 2 P rs72862282 C 0.32 0.51 0.85 9340 32314287 -‐0.102 0.007 1.2E-‐46 2 P rs62134021 C 0.48 0.09 1.00 9340 32414974 0.088 0.006 1.6E-‐46 2 P chr2:32338203:D T 0.28 0.07 0.97 9340 32338203 -‐0.100 0.007 1.6E-‐46 2 P rs55877106 T 0.48 0.02 0.99 9340 32430801 0.088 0.006 2.0E-‐46 2 P rs610758 T 0.44 0.27 1.00 9340 31833561 0.088 0.006 2.6E-‐46 2 P rs212733 T 0.40 1.35 1.00 9340 32472640 0.089 0.006 3.4E-‐46 2 P rs686005 T 0.31 0.34 0.91 9340 32493210 0.099 0.007 4.0E-‐46 2 P rs212747 A 0.33 0.49 0.97 9340 32414704 0.094 0.007 4.1E-‐46 2 P rs75440961 C 0.31 0.51 0.98 9340 32219573 -‐0.095 0.007 4.3E-‐46 2 P rs7592239 A 0.36 0.75 1.00 9340 32370258 -‐0.091 0.006 4.3E-‐46 2 P rs11683760 T 0.36 0.76 1.00 9340 32364093 -‐0.091 0.006 4.8E-‐46 2 P rs11124272 A 0.30 0.47 0.99 9340 32142520 -‐0.096 0.007 5.2E-‐46 2 P rs12618002 T 0.36 0.75 0.99 9340 32347715 -‐0.091 0.006 6.7E-‐46 2 P chr2:32362084:I D 0.34 0.41 0.90 9340 32362084 -‐0.097 0.007 7.9E-‐46 2 P rs12478134 G 0.30 0.37 0.97 9340 32240783 -‐0.097 0.007 8.1E-‐46 2 P rs13007972 G 0.36 0.70 1.00 9340 32350336 -‐0.090 0.006 1.1E-‐45 2 P rs12995952 T 0.36 0.73 0.99 9340 32373298 -‐0.091 0.006 1.5E-‐45 2 P chr2:32493527:I C 0.31 0.35 0.91 9340 32493527 0.098 0.007 2.9E-‐45 2 P chr2:32230471:I C 0.48 0.02 0.99 9340 32230471 -‐0.087 0.006 5.8E-‐45

20

2 P chr2:32316909:D A 0.28 0.20 0.95 9340 32316909 -‐0.099 0.007 8.7E-‐45 2 P rs35641550 G 0.35 0.46 0.97 9340 32351009 -‐0.092 0.007 9.5E-‐45 2 P rs9789593 G 0.30 0.55 0.97 9340 32381110 -‐0.095 0.007 1.2E-‐44 2 P rs61399065 A 0.29 0.86 0.97 9340 32208554 -‐0.096 0.007 1.2E-‐44 2 P rs41280625 T 0.48 0.07 0.99 9340 32168123 0.087 0.006 1.3E-‐44 2 P chr2:32190368:I D 0.28 0.44 0.95 9340 32190368 -‐0.097 0.007 2.0E-‐44 2 P rs806647 T 0.42 0.45 0.96 9340 31815480 0.089 0.006 2.3E-‐44 2 P chr2:32493529:I T 0.33 0.29 0.88 9340 32493529 0.097 0.007 2.9E-‐44 2 P rs472101 G 0.47 0.80 0.87 9340 32478916 0.091 0.007 3.4E-‐44 2 P rs11676475 T 0.48 0.04 0.97 9340 32389190 -‐0.087 0.006 4.1E-‐44 2 P rs806648 T 0.42 0.76 0.97 9340 31815396 0.087 0.006 4.7E-‐44 2 P rs9752651 C 0.48 0.08 0.99 9340 32208449 0.086 0.006 5.1E-‐44 2 P rs4952220 C 0.44 1.00 1.00 9340 31765556 0.085 0.006 1.0E-‐43 2 P rs216544 G 0.47 0.14 0.99 9340 32318806 -‐0.086 0.006 1.0E-‐43 2 P rs212683 A 0.34 0.70 0.96 9340 32432934 0.092 0.007 1.3E-‐43 2 P rs6761417 A 0.45 0.16 0.98 9340 32355184 0.086 0.006 1.8E-‐43 2 P rs3752917 T 0.45 0.17 0.98 9340 32354973 0.086 0.006 1.9E-‐43 2 P chr2:32194493:D C 0.48 0.09 0.98 9340 32194493 0.086 0.006 2.7E-‐43 2 P rs12474598 G 0.49 0.28 0.98 9340 32390368 -‐0.085 0.006 3.1E-‐43 2 P rs212721 A 0.39 1.37 0.99 9340 32466029 0.086 0.006 4.3E-‐43 2 P rs1904489 T 0.48 0.04 0.98 9340 32131159 0.085 0.006 4.7E-‐43 2 P rs7581432 G 0.50 0.12 1.00 9340 32395315 -‐0.084 0.006 7.2E-‐43 2 P rs72863940 T 0.47 0.20 0.93 9340 32394674 -‐0.087 0.006 1.1E-‐42 2 P rs13431540 A 0.50 0.15 0.98 9340 32334853 0.085 0.006 1.1E-‐42 2 P chr2:32359532:I D 0.48 0.11 0.89 9340 32359532 0.089 0.007 1.2E-‐42 2 P rs10208246 A 0.46 0.11 1.00 9340 32386659 0.084 0.006 1.7E-‐42 2 P rs6716179 A 0.50 0.07 1.00 9340 32393076 -‐0.084 0.006 2.2E-‐42 2 P rs2366736 C 0.49 0.11 0.97 9340 32392448 -‐0.085 0.006 2.3E-‐42

21

2 P chr2:32385895:D T 0.50 0.02 1.00 9340 32385895 -‐0.084 0.006 2.4E-‐42 2 P rs12997026 T 0.50 0.03 1.00 9340 32394307 -‐0.084 0.006 2.6E-‐42 2 P rs2280973 A 0.47 0.12 0.99 9340 32378604 0.084 0.006 2.8E-‐42 2 P rs212742 T 0.31 1.15 0.97 9340 32408629 0.091 0.007 2.9E-‐42 2 P rs467523 G 0.47 0.04 1.00 9340 32301631 -‐0.084 0.006 3.2E-‐42 2 P rs3851308 G 0.47 0.16 0.99 9340 32346493 0.084 0.006 3.3E-‐42 2 P rs212759 T 0.37 0.53 0.98 9340 32426822 0.087 0.006 3.7E-‐42 2 P rs56208031 C 0.47 0.14 1.00 9340 32345563 0.084 0.006 5.8E-‐42 2 P rs502139 T 0.33 0.68 1.00 9340 31811268 0.088 0.007 5.9E-‐42 2 P rs454119 A 0.48 0.13 0.98 9340 32302080 -‐0.085 0.006 6.2E-‐42 2 P rs212755 G 0.50 0.05 1.00 9340 32424019 0.083 0.006 6.6E-‐42 2 P rs10779914 A 0.30 0.71 1.00 9340 32106040 -‐0.091 0.007 7.4E-‐42 2 P chr2:32486389:D D 0.35 0.26 0.92 9340 32486389 0.091 0.007 1.1E-‐41 2 P rs113402659 C 0.46 0.10 0.95 9340 32191796 0.086 0.006 1.4E-‐41 2 P rs212758 A 0.37 0.52 0.98 9340 32425982 0.086 0.006 1.5E-‐41 2 P rs212749 T 0.50 0.04 1.00 9340 32415977 0.083 0.006 1.7E-‐41 2 P rs7587666 T 0.30 0.78 1.00 9340 32055890 -‐0.091 0.007 2.1E-‐41 2 P rs212700 A 0.38 0.91 1.00 9340 32443869 0.085 0.006 2.8E-‐41 2 P rs216538 G 0.47 0.07 0.99 9340 32290331 -‐0.083 0.006 4.2E-‐41 2 P chr2:32292049:D A 0.29 0.68 0.81 9340 32292049 -‐0.100 0.007 4.7E-‐41 2 P rs655548 A 0.33 0.46 1.00 9340 31836658 0.088 0.007 6.4E-‐41 2 P chr2:32050493:D G 0.28 0.59 0.96 9340 32050493 -‐0.093 0.007 1.1E-‐40 2 P rs499362 A 0.35 0.68 1.00 9340 31811572 0.086 0.006 1.3E-‐40 2 P rs1119292 T 0.30 0.71 0.99 9340 32045773 -‐0.090 0.007 1.4E-‐40 2 P rs2754530 T 0.33 0.86 1.00 9340 31803403 0.087 0.007 1.4E-‐40 2 P rs111490936 G 0.46 0.22 0.96 9340 32191789 0.084 0.006 1.5E-‐40 2 P rs10439444 T 0.46 0.01 0.99 9340 32183767 0.083 0.006 1.6E-‐40 2 P rs62142079 T 0.45 0.14 0.99 9340 32178752 0.083 0.006 1.6E-‐40

22

2 P rs4952244 A 0.30 0.64 0.99 9340 32036625 -‐0.090 0.007 1.9E-‐40 2 P rs1986134 T 0.46 0.21 0.96 9340 32138312 0.084 0.006 2.0E-‐40 2 P rs2268799 T 0.33 0.83 1.00 9340 31803495 0.087 0.007 2.2E-‐40 2 P rs806645 T 0.33 0.87 1.00 9340 31807940 0.086 0.007 3.6E-‐40 2 P rs599300 G 0.35 0.68 1.00 9340 31811306 0.086 0.006 4.6E-‐40 2 P rs1272585 C 0.49 0.06 0.99 9340 32101059 0.081 0.006 1.4E-‐39 2 P rs160801 T 0.49 0.02 0.99 9340 32104754 0.081 0.006 2.5E-‐39 2 P rs12479192 T 0.30 1.21 0.98 9340 31923042 -‐0.089 0.007 4.4E-‐39 2 P chr2:31875044:D D 0.37 0.79 0.99 9340 31875044 0.083 0.006 8.3E-‐39 2 P rs681482 A 0.34 0.40 0.99 9340 31871256 0.085 0.007 1.0E-‐38 2 P rs12712324 C 0.33 0.75 0.98 9340 32058515 -‐0.086 0.007 1.3E-‐38 2 P rs1580329 G 0.32 0.35 0.99 9340 32016677 -‐0.086 0.007 2.9E-‐38 2 P rs62141223 A 0.42 2.46 0.99 9340 31717137 0.080 0.006 3.2E-‐38 2 P rs4530415 T 0.44 0.05 0.99 9340 32384434 -‐0.080 0.006 3.6E-‐38 2 P rs35978916 C 0.28 1.14 0.98 9340 32400635 -‐0.089 0.007 3.7E-‐38 2 P rs13013695 A 0.28 1.74 1.00 9340 32391231 -‐0.087 0.007 3.9E-‐38 2 P rs12470143 T 0.47 0.02 1.00 9340 31763558 0.079 0.006 6.6E-‐38 2 P rs212713 C 0.50 0.34 1.00 9340 32457537 0.079 0.006 6.7E-‐38 2 P rs75688847 C 0.31 0.40 1.00 9340 31816734 0.086 0.007 6.9E-‐38 2 P rs545303 A 0.45 0.01 0.99 9340 31813998 0.080 0.006 7.1E-‐38 2 P rs223665 C 0.49 0.08 1.00 9340 32019747 0.079 0.006 9.0E-‐38 2 P rs160803 C 0.49 0.01 0.99 9340 32056297 0.079 0.006 9.1E-‐38 2 P rs1510917 A 0.30 0.83 0.98 9340 31928899 -‐0.087 0.007 9.7E-‐38 2 P rs223627 A 0.47 0.04 1.00 9340 31975104 0.079 0.006 1.4E-‐37 2 P rs806584 C 0.49 0.18 1.00 9340 31912164 0.079 0.006 1.5E-‐37 2 P rs212690 C 0.29 1.02 1.00 9340 32437631 0.086 0.007 1.7E-‐37 2 P rs589427 A 0.32 0.71 1.00 9340 31872513 0.084 0.007 1.8E-‐37 2 P rs223621 C 0.49 0.02 1.00 9340 32030492 0.079 0.006 1.9E-‐37

23

2 P rs212696 A 0.29 0.91 1.00 9340 32441685 0.086 0.007 2.0E-‐37 2 P rs462878 A 0.29 1.08 1.00 9340 32438655 0.086 0.007 2.0E-‐37 2 P rs177082 A 0.29 1.08 1.00 9340 32438350 0.086 0.007 2.1E-‐37 2 P rs212691 G 0.29 1.10 1.00 9340 32438075 0.086 0.007 2.2E-‐37 2 P rs11678843 C 0.30 0.25 0.99 9340 31961182 -‐0.086 0.007 2.3E-‐37 2 P rs212689 G 0.29 1.06 1.00 9340 32437338 0.086 0.007 2.8E-‐37 2 P rs212694 T 0.50 0.67 0.99 9340 32438958 0.078 0.006 4.3E-‐37 2 P rs6748639 T 0.30 0.83 0.98 9340 31922672 -‐0.087 0.007 4.4E-‐37 2 P rs34835885 A 0.29 1.06 0.98 9340 32325414 -‐0.087 0.007 4.5E-‐37 2 P chr2:32086853:D A 0.30 0.29 0.97 9340 32086853 -‐0.087 0.007 5.8E-‐37 2 P rs212757 G 0.50 0.24 1.00 9340 32425078 0.078 0.006 6.5E-‐37 2 P rs223674 C 0.48 0.00 0.98 9340 32026140 0.079 0.006 6.7E-‐37 2 P rs212736 T 0.27 0.78 1.00 9340 32473126 0.087 0.007 8.2E-‐37 2 P rs62142080 C 0.40 0.27 0.99 9340 32182528 0.079 0.006 8.8E-‐37 2 P rs223629 A 0.44 0.10 1.00 9340 31973667 0.079 0.006 9.0E-‐37 2 P rs223625 C 0.47 0.09 0.97 9340 31976520 0.079 0.006 9.9E-‐37 2 P chr2:32086852:D A 0.30 0.30 0.96 9340 32086852 -‐0.087 0.007 1.0E-‐36 2 P rs1090828 T 0.49 0.11 0.99 9340 31955389 0.078 0.006 1.4E-‐36 2 P rs527112 T 0.31 0.59 0.99 9340 31865618 0.085 0.007 1.4E-‐36 2 P rs585890 T 0.47 0.02 0.99 9340 31819430 0.078 0.006 1.5E-‐36 2 P rs2280972 T 0.27 0.26 0.97 9340 32377961 -‐0.089 0.007 2.1E-‐36 2 P rs1090825 C 0.48 0.08 0.99 9340 31925767 0.078 0.006 2.4E-‐36 2 P chr2:32392416:I D 0.36 0.90 0.96 9340 32392416 0.082 0.007 2.7E-‐36 2 P rs523349 G 0.31 0.67 1.00 9340 31805706 0.084 0.007 2.8E-‐36 2 P rs2366297 A 0.46 0.18 0.99 9340 32112466 0.078 0.006 2.9E-‐36 2 P rs477517 C 0.32 0.41 0.99 9340 31848637 0.083 0.007 2.9E-‐36 2 P rs682895 T 0.31 0.49 1.00 9340 31871583 0.083 0.007 3.5E-‐36 2 P rs223647 C 0.49 0.01 0.99 9340 32001135 0.078 0.006 3.6E-‐36

24

2 P rs6726908 C 0.34 0.45 0.99 9340 32008223 -‐0.082 0.007 3.7E-‐36 2 P rs665237 C 0.48 0.02 1.00 9340 31869943 0.077 0.006 4.1E-‐36 2 P rs223661 A 0.46 0.10 0.99 9340 32016989 0.078 0.006 4.8E-‐36 2 P rs12467911 T 0.31 0.62 1.00 9340 31782791 0.083 0.007 4.9E-‐36 2 P chr2:32366014:I D 0.37 0.33 0.90 9340 32366014 -‐0.084 0.007 5.1E-‐36 2 P rs2208528 C 0.33 0.44 0.98 9340 31828765 0.082 0.007 6.4E-‐36 2 P rs79180002 G 0.46 0.01 0.98 9340 31947837 0.078 0.006 6.9E-‐36 2 P rs12468012 A 0.30 1.17 0.98 9340 32256381 -‐0.085 0.007 7.1E-‐36 2 P rs13400554 T 0.31 0.25 0.93 9340 32227257 -‐0.086 0.007 8.6E-‐36 2 P chr2:31852498:D C 0.42 0.48 0.89 9340 31852498 0.083 0.007 9.4E-‐36 2 P rs600015 G 0.32 0.25 0.99 9340 31820300 0.082 0.007 1.0E-‐35 2 P rs28494485 A 0.26 0.13 0.74 9340 32336385 -‐0.102 0.008 1.0E-‐35 2 P chr2:31975798:D G 0.28 1.01 0.97 9340 31975798 -‐0.086 0.007 1.1E-‐35 2 P rs676033 T 0.32 0.35 1.00 9340 31808970 0.083 0.007 1.3E-‐35 2 P rs633233 C 0.33 0.54 1.00 9340 31841950 0.082 0.007 1.4E-‐35 2 P rs140958777 G 0.44 0.84 0.97 9340 31720996 0.078 0.006 1.7E-‐35 2 P chr2:31807998:I A 0.32 0.55 1.00 9340 31807998 0.082 0.007 1.7E-‐35 2 P rs632148 C 0.32 0.51 1.00 9340 31806031 0.082 0.007 1.7E-‐35 2 P rs12475443 A 0.47 0.01 1.00 9340 32071056 0.077 0.006 1.8E-‐35 2 P rs553464 G 0.38 0.44 1.00 9340 31873476 0.079 0.006 1.8E-‐35 2 P rs11526116 A 0.43 1.40 1.00 9340 31704942 0.077 0.006 2.1E-‐35 2 P rs160797 C 0.37 0.49 0.97 9340 32135957 0.080 0.006 2.1E-‐35 2 P rs481126 A 0.47 0.03 0.99 9340 31878243 0.077 0.006 2.1E-‐35 2 P rs522638 A 0.32 0.59 1.00 9340 31805675 0.082 0.007 2.4E-‐35 2 P exm2265132 A 0.43 1.16 1.00 9340 31695655 0.077 0.006 2.4E-‐35 2 P rs212710 C 0.31 0.80 0.97 9340 32455578 0.084 0.007 2.5E-‐35 2 P rs725631 A 0.32 0.38 0.98 9340 31781026 0.083 0.007 2.7E-‐35 2 P rs11124266 C 0.34 0.88 0.99 9340 31918564 -‐0.081 0.007 2.7E-‐35

25

2 P rs11695295 C 0.34 0.71 1.00 9340 31973127 -‐0.081 0.007 3.0E-‐35 2 P rs11683744 T 0.29 0.54 1.00 9340 31985308 -‐0.084 0.007 3.1E-‐35 2 P rs11124260 A 0.43 1.24 1.00 9340 31698342 0.076 0.006 3.2E-‐35 2 P rs6709048 T 0.38 0.18 0.93 9340 32381109 0.081 0.007 3.8E-‐35 2 P rs569320 T 0.30 0.45 0.99 9340 31868047 0.083 0.007 4.3E-‐35 2 P rs142131665 T 0.45 0.98 0.98 9340 31716196 0.077 0.006 4.4E-‐35 2 P rs1006070 C 0.43 1.41 1.00 9340 31689356 0.076 0.006 4.9E-‐35 2 P rs78357586 T 0.34 0.43 0.99 9340 31840821 0.081 0.007 6.0E-‐35 2 P rs534999 C 0.32 0.70 0.99 9340 31844504 0.081 0.007 6.4E-‐35 2 P rs546935 A 0.32 0.30 0.99 9340 31853674 0.082 0.007 6.4E-‐35 2 P rs614173 C 0.32 0.27 0.99 9340 31853202 0.082 0.007 6.7E-‐35 2 P rs4952215 G 0.44 1.27 0.98 9340 31715048 0.077 0.006 7.1E-‐35 2 P rs558803 C 0.32 0.66 0.99 9340 31844800 0.081 0.007 7.2E-‐35 2 P rs4952207 T 0.42 0.24 0.99 9340 32383078 -‐0.078 0.006 7.2E-‐35 2 P rs177083 C 0.48 0.34 1.00 9340 32447718 0.076 0.006 8.6E-‐35 2 P chr2:32099987:I D 0.32 0.56 0.97 9340 32099987 -‐0.082 0.007 1.3E-‐34 2 P rs223631 T 0.49 0.01 1.00 9340 31986063 0.075 0.006 1.5E-‐34 2 P rs13017027 T 0.27 2.04 0.99 9340 32291903 -‐0.085 0.007 1.6E-‐34 2 P rs56861054 C 0.35 0.58 0.95 9340 32459091 0.080 0.007 1.6E-‐34 2 P rs212704 C 0.48 0.33 1.00 9340 32450348 0.075 0.006 1.7E-‐34 2 P rs564310 G 0.49 0.04 0.99 9340 31892342 0.076 0.006 1.9E-‐34 2 P rs2366070 C 0.36 1.11 0.99 9340 31908158 -‐0.079 0.006 2.2E-‐34 2 P rs7569264 C 0.26 0.25 0.96 9340 32316921 -‐0.088 0.007 2.2E-‐34 2 P rs13006880 A 0.28 1.82 0.99 9340 32355539 -‐0.084 0.007 2.3E-‐34 2 P rs57903075 T 0.44 0.96 0.97 9340 32469618 0.076 0.006 2.8E-‐34 2 P chr2:31888571:D T 0.48 0.04 0.97 9340 31888571 0.076 0.006 3.3E-‐34 2 P rs212702 A 0.28 1.87 0.99 9340 32444250 0.083 0.007 3.8E-‐34 2 P rs115002053 A 0.43 0.01 0.99 9340 31905563 0.076 0.006 4.1E-‐34

26

2 P chr2:31837367:D D 0.44 0.71 0.96 9340 31837367 0.076 0.006 5.6E-‐34 2 P rs646674 A 0.30 0.30 0.97 9340 31815844 0.083 0.007 5.7E-‐34 2 P rs652894 G 0.39 0.12 0.99 9340 31836076 0.077 0.006 7.0E-‐34 2 P rs12479415 T 0.40 1.87 0.99 9340 31718439 0.076 0.006 8.4E-‐34 2 P rs59894106 A 0.43 0.37 0.99 9340 31773433 0.076 0.006 1.1E-‐33 2 P rs481344 A 0.31 0.34 0.99 9340 31859919 0.081 0.007 1.2E-‐33 2 P rs212752 T 0.47 0.01 0.98 9340 32419903 0.075 0.006 1.6E-‐33 2 P rs11904162 G 0.34 0.90 1.00 9340 32070489 -‐0.079 0.007 1.6E-‐33 2 P rs4952235 G 0.33 0.37 1.00 9340 31978545 -‐0.079 0.007 1.7E-‐33 2 P rs34474809 T 0.27 0.11 0.87 9340 32318374 -‐0.090 0.007 2.2E-‐33 2 P chr2:31686965:I G 0.43 1.38 0.99 9340 31686965 0.075 0.006 2.5E-‐33 2 P rs11676456 G 0.27 2.09 0.99 9340 32331511 -‐0.083 0.007 2.6E-‐33 2 P rs11124270 A 0.28 1.16 0.99 9340 32003345 -‐0.082 0.007 3.2E-‐33 2 P rs2300699 G 0.34 0.29 1.00 9340 31786967 0.078 0.007 3.3E-‐33 2 P rs508562 G 0.43 0.73 0.96 9340 31837368 0.076 0.006 3.7E-‐33 2 P rs490457 A 0.33 0.51 1.00 9340 31839106 0.079 0.007 3.8E-‐33 2 P rs539213 G 0.35 1.04 0.99 9340 31876492 0.077 0.006 4.4E-‐33 2 P rs1978824 C 0.27 2.40 0.98 9340 32167841 -‐0.083 0.007 5.9E-‐33 2 P rs10153876 C 0.29 1.20 0.99 9340 32011477 -‐0.081 0.007 7.5E-‐33 2 P rs607294 T 0.33 0.07 1.00 9340 31832807 0.079 0.007 1.2E-‐32 2 P rs809364 A 0.31 0.43 0.95 9340 31815453 0.081 0.007 1.4E-‐32 2 P chr2:32449879:I T 0.49 0.35 0.98 9340 32449879 0.074 0.006 1.8E-‐32 2 P rs4258846 T 0.35 0.26 0.97 9340 32402636 0.077 0.007 2.6E-‐32 2 P rs1978638 T 0.41 1.68 0.99 9340 31633014 0.074 0.006 3.2E-‐32 2 P rs2082185 G 0.27 2.40 0.98 9340 32155175 -‐0.082 0.007 4.4E-‐32 2 P rs149051613 C 0.44 0.79 0.96 9340 31721342 0.074 0.006 5.8E-‐32 2 P rs1090821 T 0.41 0.15 0.93 9340 31915712 0.077 0.007 6.3E-‐32 2 P rs223630 C 0.49 0.06 0.99 9340 31988435 0.073 0.006 6.8E-‐32

27

2 P rs520041 T 0.33 0.64 0.98 9340 31896249 -‐0.077 0.007 8.5E-‐32 2 P rs7575607 G 0.40 1.93 1.00 9340 31640455 0.073 0.006 1.0E-‐31 2 P rs17545406 T 0.40 1.78 1.00 9340 31653405 0.073 0.006 1.2E-‐31 2 P rs1090846 T 0.30 0.38 0.98 9340 31816341 0.080 0.007 1.2E-‐31 2 P chr2:31893545:I D 0.49 0.16 0.95 9340 31893545 0.074 0.006 1.5E-‐31 2 P rs58067528 G 0.42 0.95 1.00 9340 31678153 0.073 0.006 1.5E-‐31 2 P rs28810790 C 0.42 1.64 0.96 9340 31718354 0.074 0.006 1.6E-‐31 2 P rs493162 T 0.43 0.24 0.99 9340 31864211 0.073 0.006 1.9E-‐31 2 P rs1033690 T 0.42 0.91 1.00 9340 31695806 0.072 0.006 2.5E-‐31 2 P rs62141168 T 0.42 0.98 1.00 9340 31678065 0.072 0.006 2.7E-‐31 2 P rs2300700 A 0.46 0.04 1.00 9340 31786992 0.072 0.006 2.9E-‐31 2 P rs623419 A 0.33 0.00 1.00 9340 31834078 0.077 0.007 3.1E-‐31 2 P rs188703285 G 0.42 1.00 0.99 9340 31722533 0.072 0.006 3.2E-‐31 2 P rs518923 C 0.36 0.36 0.99 9340 31839956 0.075 0.006 4.7E-‐31 2 P rs183807535 T 0.27 0.72 0.91 9340 32276079 -‐0.084 0.007 5.1E-‐31 2 P rs75125240 C 0.43 0.75 0.98 9340 31724446 0.073 0.006 5.1E-‐31 2 P rs223675 A 0.31 2.17 0.93 9340 32026249 0.079 0.007 5.7E-‐31 2 P rs212756 A 0.45 0.05 0.98 9340 32424288 0.072 0.006 6.8E-‐31 2 P rs633376 T 0.29 0.33 0.98 9340 31815191 0.079 0.007 1.3E-‐30 2 P rs11695080 C 0.24 1.25 0.95 9340 32316886 -‐0.084 0.007 1.8E-‐30 2 P rs644103 G 0.36 0.14 0.99 9340 31855321 0.074 0.006 3.3E-‐30 2 P rs55730514 T 0.36 1.01 0.97 9340 32129718 0.074 0.006 4.0E-‐30 2 P rs1817437 T 0.30 0.91 0.99 9340 32016460 -‐0.077 0.007 4.8E-‐30 2 P rs524345 T 0.34 0.32 1.00 9340 31833976 0.074 0.007 5.0E-‐30 2 P rs206811 A 0.37 1.06 1.00 9340 31636915 0.072 0.006 7.3E-‐30 2 P rs58967340 T 0.42 1.00 1.00 9340 31697681 0.071 0.006 7.3E-‐30 2 P rs72863937 A 0.43 0.29 0.99 9340 32388923 -‐0.071 0.006 8.2E-‐30 2 P rs376751 A 0.31 0.41 0.91 9340 32494962 0.079 0.007 8.9E-‐30

28

2 P rs66985656 C 0.36 0.99 0.99 9340 31994983 0.073 0.006 9.6E-‐30 2 P rs212706 A 0.45 0.48 0.98 9340 32451132 0.070 0.006 1.6E-‐29 2 P rs212707 C 0.45 0.48 0.98 9340 32451148 0.070 0.006 1.6E-‐29 2 P rs212708 A 0.45 0.48 0.98 9340 32451446 0.070 0.006 1.7E-‐29 2 P rs608574 G 0.35 0.15 0.99 9340 31833066 0.073 0.007 1.9E-‐29 2 P rs12467131 T 0.45 1.47 0.98 9340 31718660 0.070 0.006 2.3E-‐29 2 P rs28383018 C 0.35 0.40 0.97 9340 31772481 0.074 0.007 2.7E-‐29 2 P rs17604588 G 0.41 1.20 1.00 9340 31649666 0.070 0.006 2.7E-‐29 2 P rs160805 G 0.36 0.58 1.00 9340 32057791 0.072 0.006 3.5E-‐29 2 P rs621357 G 0.37 0.11 0.99 9340 31841592 0.072 0.006 3.8E-‐29 2 P rs28797569 T 0.36 0.55 1.00 9340 32055586 0.072 0.006 3.9E-‐29 2 P chr2:31727520:I A 0.33 0.49 0.95 9340 31727520 0.075 0.007 4.6E-‐29 2 P rs206843 T 0.31 1.10 0.99 9340 31719128 0.074 0.007 6.2E-‐29 2 P rs160804 T 0.36 0.66 1.00 9340 32057759 0.071 0.006 6.7E-‐29 2 P rs4952203 A 0.26 1.82 1.00 9340 32103689 -‐0.078 0.007 7.5E-‐29 2 P rs654265 G 0.36 0.25 0.99 9340 31829825 0.072 0.006 7.6E-‐29 2 P rs660558 G 0.35 0.16 0.99 9340 31850035 0.073 0.007 7.9E-‐29 2 P rs34514981 C 0.26 1.88 0.99 9340 32043947 -‐0.078 0.007 8.1E-‐29 2 P rs212705 G 0.47 0.60 0.97 9340 32450508 0.070 0.006 8.1E-‐29 2 P rs57971483 C 0.34 0.31 0.98 9340 31765510 0.073 0.007 1.0E-‐28 2 P rs138946679 A 0.39 0.61 0.93 9340 31721838 0.072 0.007 1.7E-‐28 2 P chr2:32286411:I D 0.45 0.14 0.90 9340 32286411 -‐0.072 0.007 2.1E-‐28 2 P rs60962780 A 0.26 1.94 0.98 9340 32034703 -‐0.078 0.007 2.4E-‐28 2 P rs58364223 G 0.46 1.32 0.99 9340 31717414 0.068 0.006 2.5E-‐28 2 P rs55819371 C 0.44 0.96 0.96 9340 31720678 0.069 0.006 4.4E-‐28 2 P rs3754835 T 0.40 0.17 1.00 9340 32206029 0.069 0.006 4.5E-‐28 2 P rs55764678 C 0.36 0.71 0.99 9340 31978803 0.070 0.006 4.9E-‐28 2 P rs206840 C 0.31 1.26 0.99 9340 31717127 0.073 0.007 5.0E-‐28

29

2 P rs55796887 C 0.48 0.34 0.98 9340 32431017 0.069 0.006 5.1E-‐28 2 P rs191528674 A 0.13 0.14 0.76 9340 32336333 -‐0.114 0.010 5.1E-‐28 2 P rs59255043 C 0.35 0.31 0.97 9340 31853295 0.072 0.007 5.3E-‐28 2 P rs206816 T 0.40 0.68 1.00 9340 31644983 0.069 0.006 5.9E-‐28 2 P chr2:31983155:D C 0.34 0.35 0.99 9340 31983155 0.071 0.007 6.6E-‐28 2 P rs6752375 T 0.31 0.59 1.00 9340 32247942 0.073 0.007 7.2E-‐28 2 P rs223649 T 0.32 0.13 0.97 9340 32004450 0.073 0.007 1.1E-‐27 2 P rs2208158 T 0.29 0.87 0.99 9340 31742862 0.074 0.007 1.1E-‐27 2 P rs56175176 T 0.29 0.79 1.00 9340 31741566 0.073 0.007 1.7E-‐27 2 P rs2224310 C 0.30 0.97 1.00 9340 31742467 0.073 0.007 2.0E-‐27 2 P rs1475054 G 0.29 0.83 1.00 9340 31741965 0.073 0.007 2.0E-‐27 2 P chr2:31971583:D T 0.32 0.34 0.98 9340 31971583 0.072 0.007 2.1E-‐27 2 P rs6760199 A 0.29 0.77 1.00 9340 31742278 0.073 0.007 2.1E-‐27 2 P rs6739055 G 0.31 1.05 1.00 9340 32071502 -‐0.073 0.007 2.1E-‐27 2 P rs206806 T 0.39 0.74 0.99 9340 31633965 0.068 0.006 3.8E-‐27 2 P rs12473298 C 0.47 1.48 1.00 9340 31702502 0.066 0.006 8.9E-‐27 2 P rs142669186 A 0.49 0.18 0.91 9340 31724549 0.069 0.006 9.1E-‐27 2 P rs426723 T 0.43 0.31 0.96 9340 31744130 0.068 0.006 9.5E-‐27 2 P rs559555 T 0.44 0.13 0.99 9340 31810974 0.067 0.006 1.4E-‐26 2 P rs671742 C 0.34 0.14 0.97 9340 31856868 0.071 0.007 1.5E-‐26 2 P rs669347 T 0.28 1.08 0.99 9340 31830912 0.073 0.007 1.6E-‐26 2 P rs612224 C 0.31 0.96 1.00 9340 31811870 0.071 0.007 1.8E-‐26 2 P chr2:31737481:I D 0.33 0.68 0.97 9340 31737481 0.070 0.007 1.8E-‐26 2 P rs6543630 A 0.30 0.53 1.00 9340 31740034 0.072 0.007 1.8E-‐26 2 P rs206842 A 0.33 0.59 0.96 9340 31718031 0.071 0.007 2.6E-‐26 2 P rs206854 A 0.33 1.80 1.00 9340 31616749 0.069 0.007 3.1E-‐26 2 P rs55744195 C 0.43 0.83 0.99 9340 31720770 0.066 0.006 3.1E-‐26 2 P rs206835 A 0.33 0.68 0.99 9340 31711405 0.070 0.007 4.3E-‐26

30

2 P rs806646 A 0.30 1.80 0.90 9340 31816197 0.074 0.007 4.4E-‐26 2 P rs206839 C 0.33 0.68 0.99 9340 31714558 0.070 0.007 4.5E-‐26 2 P rs4952218 A 0.31 0.39 0.99 9340 31731120 0.071 0.007 4.6E-‐26 2 P rs56271553 T 0.32 0.39 0.94 9340 31718418 0.072 0.007 4.7E-‐26 2 P rs3952614 T 0.43 0.71 0.98 9340 31720306 0.066 0.006 5.1E-‐26 2 P rs183415224 T 0.34 0.59 0.95 9340 31968206 0.070 0.007 8.5E-‐26 2 P rs6732223 T 0.49 0.61 0.99 9340 31742662 0.065 0.006 1.2E-‐25 2 P rs61316601 T 0.43 0.95 0.99 9340 31719272 0.065 0.006 1.2E-‐25 2 P rs6543631 C 0.49 0.68 0.99 9340 31742987 0.065 0.006 1.2E-‐25 2 P chr2:31742896:I D 0.49 0.68 0.99 9340 31742896 0.064 0.006 1.7E-‐25 2 P rs1884723 G 0.47 1.19 1.00 9340 31699883 0.064 0.006 1.7E-‐25 2 P rs72794621 T 0.43 0.93 1.00 9340 31730255 0.064 0.006 1.9E-‐25 2 P rs185925 G 0.34 2.51 1.00 9340 31609993 0.067 0.006 2.1E-‐25 2 P rs206845 A 0.33 1.14 0.95 9340 31719723 0.069 0.007 2.8E-‐25 2 P rs72794610 A 0.46 0.95 1.00 9340 31694558 0.064 0.006 3.7E-‐25 2 P rs4952239 A 0.34 2.39 1.00 9340 31609961 0.067 0.006 4.0E-‐25 2 P rs11526117 G 0.31 0.37 0.96 9340 31705174 0.070 0.007 4.1E-‐25 2 P chr2:32337079:D T 0.33 1.45 0.73 9340 32337079 0.079 0.008 4.3E-‐25 2 P rs67603251 G 0.46 1.16 1.00 9340 31680623 0.064 0.006 5.0E-‐25 2 P rs60441502 T 0.46 0.95 1.00 9340 31699012 0.064 0.006 5.3E-‐25 2 P rs4622775 C 0.42 0.19 0.97 9340 31667530 0.065 0.006 5.7E-‐25 2 P rs2365778 C 0.48 0.78 1.00 9340 31738219 0.063 0.006 6.1E-‐25 2 P rs17545760 A 0.46 0.82 1.00 9340 31671658 0.063 0.006 8.5E-‐25 2 P rs206859 A 0.37 1.83 1.00 9340 31619559 0.065 0.006 9.9E-‐25 2 P rs766273 G 0.46 0.67 1.00 9340 31670523 0.063 0.006 1.0E-‐24 2 P rs55933129 T 0.46 0.82 1.00 9340 31663470 0.063 0.006 1.5E-‐24 2 P rs55679051 T 0.33 0.08 0.97 9340 31866595 0.068 0.007 1.6E-‐24 2 P rs143972765 G 0.42 0.71 0.97 9340 31724470 0.064 0.006 1.8E-‐24

31

2 P rs4952263 A 0.46 1.18 1.00 9340 31705611 0.063 0.006 2.4E-‐24 2 P rs4952197 A 0.27 1.60 0.98 9340 31767131 0.071 0.007 2.6E-‐24 2 P rs7585845 C 0.46 0.78 1.00 9340 31669627 0.063 0.006 2.7E-‐24 2 P rs28815209 T 0.46 0.71 1.00 9340 31662319 0.063 0.006 3.1E-‐24 2 P rs1033689 T 0.45 0.79 1.00 9340 31695729 0.062 0.006 4.9E-‐24 2 P rs9636426 T 0.45 0.84 1.00 9340 31711497 0.062 0.006 5.9E-‐24 2 P chr2:31693430:D A 0.45 1.00 1.00 9340 31693430 0.062 0.006 7.8E-‐24 2 P rs56148003 T 0.41 0.39 0.99 9340 31733256 0.063 0.006 8.2E-‐24 2 P rs6749019 C 0.46 0.13 0.99 9340 31797811 0.063 0.006 8.6E-‐24 2 P rs206827 T 0.36 0.45 1.00 9340 31686309 0.064 0.006 9.2E-‐24 2 P rs7602067 A 0.46 1.16 1.00 9340 31698440 0.062 0.006 9.8E-‐24 2 P rs55708293 T 0.45 0.81 1.00 9340 31676252 0.062 0.006 9.8E-‐24 2 P rs2064813 G 0.20 0.49 1.00 9340 32212935 -‐0.077 0.008 9.9E-‐24 2 P rs56247470 T 0.45 0.86 1.00 9340 31698691 0.062 0.006 1.0E-‐23 2 P rs4952251 A 0.46 0.78 1.00 9340 31682549 0.062 0.006 1.0E-‐23 2 P rs11124261 A 0.45 0.86 1.00 9340 31698519 0.062 0.006 1.1E-‐23 2 P rs206837 C 0.34 0.55 0.97 9340 31711757 0.066 0.007 1.2E-‐23 2 P rs1366815 T 0.45 1.00 1.00 9340 31690821 0.062 0.006 1.2E-‐23 2 P rs56406022 T 0.41 0.36 0.99 9340 31733657 0.063 0.006 1.3E-‐23 2 P rs10207755 C 0.42 0.10 0.99 9340 31796970 0.063 0.006 1.3E-‐23 2 P rs761925 A 0.45 1.00 1.00 9340 31693451 0.062 0.006 1.4E-‐23 2 P rs191882 C 0.36 0.36 0.94 9340 31721380 0.066 0.007 1.6E-‐23 2 P rs212712 C 0.48 0.58 0.81 9340 32456643 0.068 0.007 1.7E-‐23 2 P rs1114962 T 0.45 0.79 1.00 9340 31675248 0.062 0.006 1.8E-‐23 2 P rs635304 T 0.31 0.16 0.96 9340 31867905 0.068 0.007 1.8E-‐23 2 P rs72794604 C 0.45 0.82 1.00 9340 31677758 0.062 0.006 1.9E-‐23 2 P rs60151591 T 0.45 1.03 1.00 9340 31692459 0.061 0.006 1.9E-‐23 2 P rs59964343 T 0.48 1.21 1.00 9340 31650161 0.061 0.006 2.1E-‐23

32

2 P rs206847 T 0.36 1.53 1.00 9340 31611367 0.064 0.006 2.8E-‐23 2 P rs28879135 T 0.45 0.81 0.99 9340 31662335 0.061 0.006 3.4E-‐23 2 P rs11684698 A 0.37 0.35 0.91 9340 31727524 0.066 0.007 3.9E-‐23 2 P rs6758752 G 0.30 1.58 0.98 9340 31729933 0.067 0.007 4.0E-‐23 2 P rs17545483 T 0.45 0.71 1.00 9340 31663803 0.061 0.006 4.8E-‐23 2 P rs17604831 A 0.45 0.76 1.00 9340 31664302 0.061 0.006 4.9E-‐23 2 P rs12468955 C 0.45 0.77 1.00 9340 31667253 0.061 0.006 5.7E-‐23 2 P rs206858 G 0.38 1.42 0.99 9340 31619267 0.063 0.006 6.7E-‐23 2 P rs145936950 A 0.16 0.36 0.77 9340 32336299 -‐0.093 0.009 8.5E-‐23 2 P rs206822 G 0.39 0.00 0.99 9340 31674740 0.063 0.006 8.9E-‐23 2 P rs6727873 C 0.16 0.51 0.89 9340 32306466 -‐0.088 0.009 9.8E-‐23 2 P rs765138 T 0.40 0.09 1.00 9340 31803939 0.062 0.006 1.0E-‐22 2 P rs112810470 A 0.31 0.18 0.96 9340 31634012 0.066 0.007 1.1E-‐22 2 P chr2:31655495:I D 0.46 0.72 1.00 9340 31655495 0.060 0.006 1.1E-‐22 2 P rs138160980 G 0.43 0.53 0.97 9340 31724516 0.061 0.006 2.3E-‐22 2 P rs413836 A 0.42 0.19 0.99 9340 31758047 0.061 0.006 2.7E-‐22 2 P chr2:31687566:D G 0.45 1.20 0.98 9340 31687566 0.060 0.006 2.9E-‐22 2 P rs2300697 C 0.43 0.01 1.00 9340 31786637 0.060 0.006 3.8E-‐22 2 P rs55715432 T 0.32 0.04 0.95 9340 31672777 0.065 0.007 5.1E-‐22 2 P rs12469125 A 0.48 0.88 1.00 9340 31702606 0.059 0.006 6.3E-‐22 2 P rs11894988 A 0.27 0.86 0.95 9340 31745905 -‐0.068 0.007 1.0E-‐21 2 P rs2300701 A 0.43 0.05 1.00 9340 31787008 0.060 0.006 1.0E-‐21 2 P rs2300698 A 0.43 0.06 1.00 9340 31786793 0.060 0.006 1.1E-‐21 2 P rs66492775 T 0.46 0.72 1.00 9340 31647169 0.059 0.006 1.2E-‐21 2 P rs2208532 G 0.44 0.20 0.99 9340 31788989 0.059 0.006 2.3E-‐21 2 P rs180831142 C 0.40 0.91 0.85 9340 31726996 0.064 0.007 2.8E-‐21 2 P rs1978639 A 0.48 0.83 0.99 9340 31632956 0.058 0.006 3.9E-‐21 2 P rs58071748 T 0.46 0.99 1.00 9340 31652351 0.058 0.006 4.5E-‐21

33

2 P rs138904599 A 0.20 0.59 0.86 9340 32326165 0.080 0.008 4.6E-‐21 2 P rs80205991 T 0.46 1.08 1.00 9340 31642241 0.058 0.006 4.9E-‐21 2 P rs67830899 T 0.45 0.69 1.00 9340 31657580 0.058 0.006 5.5E-‐21 2 P rs7595578 T 0.45 0.63 1.00 9340 31656380 0.058 0.006 7.3E-‐21 2 P rs4952236 T 0.45 0.72 1.00 9340 31644939 0.058 0.006 9.8E-‐21 2 P rs72790682 T 0.44 0.70 0.98 9340 31657661 0.058 0.006 1.1E-‐20 2 P rs62142112 T 0.19 0.68 0.87 9340 32337492 0.079 0.009 1.6E-‐20 2 P rs206826 C 0.31 1.04 1.00 9340 31683940 0.062 0.007 1.8E-‐20 2 P rs11679875 A 0.47 0.85 1.00 9340 31707054 0.057 0.006 2.1E-‐20 2 P rs61706447 T 0.48 0.72 0.99 9340 31633438 0.057 0.006 2.2E-‐20 2 P chr2:31943991:I D 0.29 2.00 0.97 9340 31943991 -‐0.063 0.007 2.7E-‐20 2 P rs60989770 C 0.40 0.68 0.99 9340 31700393 0.058 0.006 3.2E-‐20 2 P rs11687212 G 0.47 0.69 1.00 9340 31676320 0.057 0.006 3.5E-‐20 2 P rs1835169 T 0.47 0.64 0.99 9340 31691829 0.057 0.006 5.5E-‐20 2 P rs2073316 A 0.47 0.67 1.00 9340 31611029 0.056 0.006 5.5E-‐20 2 P rs4952219 A 0.43 0.17 0.99 9340 31734916 0.057 0.006 5.6E-‐20 2 P rs206823 G 0.32 0.94 0.99 9340 31675311 0.061 0.007 6.7E-‐20 2 P rs2365772 T 0.47 0.64 1.00 9340 31659226 0.056 0.006 1.8E-‐19 2 P rs68051008 A 0.47 0.69 1.00 9340 31678018 0.056 0.006 2.1E-‐19 2 P rs59770035 A 0.48 0.76 0.99 9340 31668113 0.055 0.006 3.1E-‐19 2 P rs206790 A 0.31 1.28 0.98 9340 31662377 0.060 0.007 3.3E-‐19 2 P rs206792 G 0.31 1.10 0.99 9340 31665707 0.060 0.007 3.5E-‐19 2 P exm184959 A 0.00 0.00 0.99 9340 32463365 -‐0.445 0.050 5.8E-‐19 2 P rs438408 G 0.38 0.43 1.00 9340 32495395 0.056 0.006 9.4E-‐19 2 P rs1429372 G 0.44 0.48 0.98 9340 31626385 0.055 0.006 1.1E-‐18 2 P rs61144237 A 0.14 1.23 0.93 9340 32150343 -‐0.080 0.009 2.0E-‐18 2 P rs206821 A 0.30 1.12 0.99 9340 31656596 0.059 0.007 2.5E-‐18 2 P rs11674100 A 0.48 0.64 1.00 9340 31657292 0.053 0.006 6.3E-‐18

34

2 P rs112067196 G 0.00 0.00 0.94 9340 32360852 -‐0.416 0.050 5.5E-‐17 2 P rs189402358 A 0.00 0.00 0.94 9340 32269307 -‐0.471 0.056 7.7E-‐17 2 P rs206851 A 0.29 1.26 0.98 9340 31614082 0.057 0.007 8.4E-‐17 2 P chr2:32341309 G 0.00 0.00 0.98 9340 32341309 -‐0.447 0.054 8.8E-‐17 2 P rs191543843 A 0.00 0.00 0.98 9340 32426321 -‐0.445 0.053 9.1E-‐17 2 P rs35369518 C 0.12 0.48 0.92 9340 32253487 -‐0.083 0.010 1.2E-‐16 2 P rs6710918 C 0.40 0.84 0.88 9340 31679168 0.055 0.007 1.2E-‐16 2 P rs206812 T 0.49 0.30 0.99 9340 31637869 0.051 0.006 1.8E-‐16 2 P rs6723226 G 0.40 1.45 1.00 9340 32849207 -‐0.051 0.006 2.5E-‐16 2 P rs1153122 T 0.38 1.17 0.96 9340 32533457 0.053 0.006 3.2E-‐16 2 P rs206808 G 0.49 0.25 0.99 9340 31634130 0.051 0.006 4.0E-‐16 2 P rs141408916 C 0.01 0.00 0.84 9340 32388578 -‐0.382 0.047 4.7E-‐16 2 P rs2294177 A 0.02 0.13 0.92 9340 32353323 -‐0.209 0.026 5.7E-‐16 2 P rs6733481 C 0.12 0.54 0.91 9340 32390834 -‐0.081 0.010 5.8E-‐16 2 P rs805830 T 0.39 0.85 0.99 9340 32501475 0.051 0.006 6.4E-‐16 2 P rs2749994 T 0.33 0.87 0.95 9340 31623237 0.054 0.007 6.4E-‐16 2 P rs390480 G 0.40 0.93 1.00 9340 32510072 0.051 0.006 7.3E-‐16 2 P rs206855 T 0.48 0.00 1.00 9340 31617143 0.050 0.006 8.7E-‐16 2 P rs176401 T 0.37 0.80 0.93 9340 32636511 -‐0.053 0.007 9.6E-‐16 2 P rs387780 T 0.38 1.05 1.00 9340 32502495 0.051 0.006 1.0E-‐15 2 P chr2:32034702:D A 0.10 0.81 0.70 9340 32034702 -‐0.097 0.012 1.1E-‐15 2 P rs149808488 A 0.03 0.49 0.94 9340 31967970 -‐0.146 0.018 1.2E-‐15 2 P rs13010404 G 0.39 1.47 0.99 9340 32848854 -‐0.050 0.006 1.5E-‐15 2 P rs176415 A 0.38 0.97 1.00 9340 32649778 -‐0.050 0.006 1.7E-‐15 2 P rs74494678 C 0.02 0.13 0.95 9340 32332009 -‐0.200 0.025 1.9E-‐15 2 P rs6751221 A 0.17 0.28 0.63 9340 32308810 -‐0.081 0.010 3.1E-‐15 2 P rs13035097 G 0.39 1.78 0.99 9340 32836362 -‐0.050 0.006 3.5E-‐15 2 P rs376914 G 0.41 0.64 0.99 9340 32508393 0.050 0.006 3.9E-‐15

35

2 P rs398290 T 0.40 1.02 1.00 9340 32503526 0.049 0.006 4.0E-‐15 2 P chr2:32849224:I D 0.39 0.90 0.97 9340 32849224 -‐0.050 0.006 4.4E-‐15 2 P rs80330546 T 0.02 0.00 0.85 9340 32349809 -‐0.188 0.024 4.8E-‐15 2 P rs4019431 A 0.39 0.94 0.99 9340 32615493 -‐0.050 0.006 5.3E-‐15 2 P rs12612824 T 0.38 1.36 1.00 9340 32579759 -‐0.049 0.006 6.7E-‐15 2 P rs11694289 T 0.30 0.48 0.98 9340 32717207 0.053 0.007 8.1E-‐15 2 P rs2010704 A 0.46 0.78 0.97 9340 31622465 0.049 0.006 1.3E-‐14 2 P rs176403 A 0.39 1.32 1.00 9340 32637864 -‐0.049 0.006 1.5E-‐14 2 P rs6543646 A 0.02 0.50 0.93 9340 32267039 -‐0.196 0.025 1.5E-‐14 2 P rs35837551 A 0.41 0.90 0.97 9340 32545499 -‐0.049 0.006 1.6E-‐14 2 P rs193161863 C 0.01 0.00 0.73 9340 32336489 -‐0.317 0.041 1.8E-‐14 2 P rs62142382 A 0.16 0.22 0.86 9340 31880861 0.069 0.009 1.8E-‐14 2 P rs458628 G 0.41 0.78 0.99 9340 32515398 0.048 0.006 1.9E-‐14 2 P rs17428810 C 0.36 2.26 0.99 9340 32736043 -‐0.049 0.006 2.1E-‐14 2 P rs176400 A 0.30 0.22 1.00 9340 32633569 -‐0.052 0.007 2.4E-‐14 2 P rs12712327 T 0.37 1.70 1.00 9340 32579219 -‐0.048 0.006 2.6E-‐14 2 P rs1901355 G 0.37 2.10 0.98 9340 32835664 -‐0.049 0.006 2.8E-‐14 2 P rs419301 G 0.39 0.56 0.89 9340 32497236 0.051 0.007 2.8E-‐14 2 P rs455737 A 0.38 1.26 0.99 9340 32528234 0.048 0.006 3.2E-‐14 2 P rs13409142 C 0.40 0.84 1.00 9340 32666137 0.048 0.006 3.2E-‐14 2 P chr2:32845664:I A 0.42 1.04 0.98 9340 32845664 -‐0.048 0.006 4.2E-‐14 2 P rs185291646 C 0.02 0.11 0.91 9340 32178453 -‐0.187 0.025 5.4E-‐14 2 P rs4952255 T 0.39 1.19 1.00 9340 32507792 0.047 0.006 5.6E-‐14 2 P rs78427917 A 0.01 0.14 0.87 9340 32262919 -‐0.210 0.028 6.3E-‐14 2 P rs115041447 T 0.02 0.31 0.92 9340 32174654 -‐0.198 0.026 6.6E-‐14 2 P rs2710626 C 0.40 0.69 1.00 9340 32758754 0.047 0.006 1.3E-‐13 2 P rs10181198 A 0.38 1.30 1.00 9340 32686582 0.047 0.006 1.6E-‐13 2 P rs2710634 C 0.49 0.39 1.00 9340 32808804 0.045 0.006 1.7E-‐13

36

2 P rs75591480 G 0.40 1.10 0.99 9340 32552611 -‐0.047 0.006 1.7E-‐13 2 P rs206849 A 0.41 0.81 1.00 9340 31613249 0.046 0.006 1.8E-‐13 2 P rs2069213 C 0.40 1.22 0.99 9340 32743084 0.047 0.006 1.9E-‐13 2 P rs449348 G 0.40 1.04 0.98 9340 32499150 0.047 0.006 2.0E-‐13 2 P rs116617324 T 0.48 0.95 0.96 9340 32622709 -‐0.046 0.006 2.2E-‐13 2 P rs2754511 T 0.31 0.24 0.97 9340 32770157 0.050 0.007 2.3E-‐13 2 P rs79030701 G 0.13 0.46 0.82 9340 32160935 0.074 0.010 2.5E-‐13 2 P rs4952343 G 0.40 0.15 0.91 9340 32858637 0.048 0.007 2.6E-‐13 2 P rs13391806 C 0.31 0.33 0.98 9340 32717647 0.049 0.007 2.7E-‐13 2 P rs6743903 T 0.11 0.56 0.95 9340 31956992 -‐0.073 0.010 3.1E-‐13 2 P rs2568464 C 0.39 0.38 0.99 9340 32848658 0.046 0.006 3.2E-‐13 2 P rs190662221 A 0.01 0.00 0.92 9340 31624303 -‐0.258 0.035 3.4E-‐13 2 P rs2754523 G 0.40 0.55 0.98 9340 32837110 0.046 0.006 4.6E-‐13 2 P rs2754522 C 0.40 1.67 0.99 9340 32801257 0.046 0.006 5.1E-‐13 2 P rs17011650 T 0.01 0.83 0.98 9340 32080799 -‐0.189 0.026 5.3E-‐13 2 P rs176410 C 0.40 0.43 1.00 9340 32643437 -‐0.045 0.006 5.6E-‐13 2 P chr2:32095245:D T 0.01 1.05 0.93 9340 32095245 -‐0.203 0.028 6.2E-‐13 2 P rs114934788 A 0.01 0.93 0.93 9340 31848445 -‐0.198 0.028 6.4E-‐13 2 P rs2366894 A 0.41 1.01 0.99 9340 32713706 0.045 0.006 6.7E-‐13 2 P rs78864479 A 0.01 0.16 0.98 9340 31872416 -‐0.198 0.028 6.7E-‐13 2 P rs427177 C 0.48 0.50 0.97 9340 32537827 0.045 0.006 6.8E-‐13 2 P rs4019436 G 0.38 1.15 0.99 9340 32603640 -‐0.046 0.006 7.2E-‐13 2 P rs10182170 G 0.41 1.10 0.99 9340 32704186 0.045 0.006 7.4E-‐13 2 P rs176411 C 0.49 0.45 1.00 9340 32643528 -‐0.044 0.006 7.7E-‐13 2 P rs187238339 C 0.14 0.31 0.90 9340 32244924 -‐0.068 0.010 7.8E-‐13 2 P rs2710627 A 0.39 1.13 0.99 9340 32758627 0.045 0.006 8.0E-‐13 2 P rs62136327 C 0.40 0.53 0.98 9340 32746605 0.045 0.006 8.2E-‐13 2 P rs2243844 A 0.39 0.68 1.00 9340 32775984 0.045 0.006 8.7E-‐13

37

2 P rs176413 G 0.41 0.37 1.00 9340 32646847 -‐0.045 0.006 1.0E-‐12 2 P rs206860 G 0.29 1.51 1.00 9340 31622804 0.048 0.007 1.1E-‐12 2 P rs78120826 T 0.02 0.51 0.93 9340 31979804 -‐0.185 0.026 1.2E-‐12 2 P rs2710630 T 0.39 0.62 1.00 9340 32765997 0.045 0.006 1.5E-‐12 2 P rs62136345 T 0.39 0.99 1.00 9340 32807223 0.045 0.006 1.5E-‐12 2 P rs762023 A 0.40 0.89 0.99 9340 32713170 0.045 0.006 1.6E-‐12 2 P rs11675297 A 0.05 1.14 0.92 9340 31793419 -‐0.104 0.015 1.7E-‐12 2 P rs2599510 G 0.47 0.61 0.99 9340 32826002 0.044 0.006 1.8E-‐12 2 P rs6543658 G 0.41 1.38 0.99 9340 32718849 0.044 0.006 1.9E-‐12 2 P rs28383017 C 0.02 0.27 0.88 9340 31772642 -‐0.180 0.026 1.9E-‐12 2 P chr2:32504650:D D 0.45 0.23 0.91 9340 32504650 0.046 0.007 2.0E-‐12 2 P rs28362154 A 0.10 1.21 0.66 9340 32336332 -‐0.089 0.013 2.0E-‐12 2 P chr2:32802646:I D 0.49 0.32 0.98 9340 32802646 0.044 0.006 2.0E-‐12 2 P rs12470580 C 0.34 0.08 0.98 9340 32677941 0.047 0.007 2.1E-‐12 2 P rs4952262 G 0.44 1.85 1.00 9340 32597234 -‐0.043 0.006 2.2E-‐12 2 P rs2754520 A 0.39 1.11 1.00 9340 32810293 0.044 0.006 2.4E-‐12 2 P rs6760040 A 0.39 0.85 0.98 9340 32608201 -‐0.045 0.006 2.5E-‐12 2 P chr2:32595386:I A 0.38 0.76 0.99 9340 32595386 -‐0.045 0.006 2.5E-‐12 2 P rs2754525 T 0.38 1.07 0.99 9340 32805286 0.045 0.006 2.6E-‐12 2 P rs2145724 T 0.01 1.48 0.92 9340 32004396 -‐0.195 0.028 3.0E-‐12 2 P rs176416 A 0.40 0.76 1.00 9340 32652223 -‐0.044 0.006 3.1E-‐12 2 P chr2:32610950:I D 0.41 0.73 0.98 9340 32610950 -‐0.044 0.006 3.2E-‐12 2 P rs2250217 G 0.40 1.16 1.00 9340 32759643 0.044 0.006 3.3E-‐12 2 P rs762025 A 0.40 0.99 0.99 9340 32603805 -‐0.044 0.006 3.6E-‐12 2 P rs2249109 G 0.40 1.73 0.99 9340 32750879 0.044 0.006 4.2E-‐12 2 P rs1135484 A 0.40 0.95 0.99 9340 32749060 0.044 0.006 4.2E-‐12 2 P rs1991626 G 0.45 1.90 1.00 9340 32602450 -‐0.043 0.006 4.2E-‐12 2 P rs2754513 G 0.42 1.30 0.99 9340 32782763 0.043 0.006 4.3E-‐12

38

2 P rs10193023 G 0.40 1.20 0.99 9340 32762379 0.044 0.006 4.3E-‐12 2 P rs11678622 T 0.48 0.98 0.89 9340 32577094 -‐0.045 0.007 4.3E-‐12 2 P rs11124268 A 0.17 0.14 0.90 9340 31951731 0.060 0.009 4.4E-‐12 2 P rs2710625 A 0.40 0.87 1.00 9340 32822957 0.043 0.006 4.9E-‐12 2 P rs45564234 T 0.02 0.11 0.91 9340 31622791 -‐0.169 0.025 5.0E-‐12 2 P rs77697285 A 0.01 1.46 0.93 9340 32005589 -‐0.191 0.028 5.4E-‐12 2 P rs10172308 A 0.40 1.44 0.99 9340 32555760 -‐0.043 0.006 5.9E-‐12 2 P rs13399071 T 0.39 1.14 0.99 9340 32793783 0.044 0.006 6.2E-‐12 2 P rs67257914 A 0.39 0.98 1.00 9340 32804018 0.044 0.006 6.6E-‐12 2 P rs62136349 A 0.39 0.82 0.99 9340 32827504 0.044 0.006 6.7E-‐12 2 P rs466146 G 0.40 0.69 0.99 9340 32539236 0.043 0.006 7.6E-‐12 2 P rs2710628 C 0.41 0.96 1.00 9340 32758353 0.043 0.006 7.8E-‐12 2 P rs4952211 T 0.49 1.15 1.00 9340 32611512 -‐0.042 0.006 7.9E-‐12 2 P rs13385788 C 0.40 0.72 0.98 9340 32719692 0.044 0.006 8.0E-‐12 2 P rs2710613 G 0.41 0.93 0.99 9340 32753491 0.043 0.006 8.3E-‐12 2 P rs176404 T 0.48 0.75 1.00 9340 32638846 -‐0.042 0.006 8.7E-‐12 2 P rs76393033 G 0.01 0.85 0.99 9340 32020014 -‐0.181 0.026 8.9E-‐12 2 P rs7604035 T 0.31 0.13 0.98 9340 32540334 -‐0.046 0.007 9.3E-‐12 2 P rs433248 T 0.39 0.53 0.96 9340 32499173 0.044 0.006 9.5E-‐12 2 P rs176405 G 0.40 0.76 0.99 9340 32639198 -‐0.043 0.006 9.6E-‐12 2 P rs444226 A 0.39 0.53 0.96 9340 32499167 0.044 0.006 9.6E-‐12 2 P rs2710606 A 0.39 1.61 0.99 9340 32811909 0.043 0.006 1.0E-‐11 2 P rs6755811 T 0.37 0.97 0.96 9340 32549230 -‐0.044 0.007 1.0E-‐11 2 P rs2710615 T 0.40 0.92 0.99 9340 32791222 0.043 0.006 1.0E-‐11 2 P rs57785053 T 0.26 1.08 0.97 9340 32504735 -‐0.048 0.007 1.1E-‐11 2 P rs7582322 C 0.40 0.52 0.95 9340 32565001 -‐0.044 0.006 1.2E-‐11 2 P rs1033751 T 0.47 0.49 0.99 9340 32695759 0.042 0.006 1.2E-‐11 2 P rs3769611 A 0.21 1.64 1.00 9340 32128601 -‐0.052 0.008 1.3E-‐11

39

2 P chr2:32783387:I D 0.30 0.16 0.93 9340 32783387 0.047 0.007 1.4E-‐11 2 P chr2:32611511:D T 0.49 1.18 0.99 9340 32611511 -‐0.042 0.006 1.4E-‐11 2 P rs4549138 A 0.35 0.94 0.99 9340 31596519 0.044 0.007 1.4E-‐11 2 P rs206846 C 0.42 0.86 1.00 9340 31610311 0.043 0.006 1.4E-‐11 2 P rs58852184 T 0.41 0.96 0.99 9340 32729763 0.043 0.006 1.5E-‐11 2 P rs437764 T 0.39 0.62 0.99 9340 32516378 0.043 0.006 1.5E-‐11 2 P rs2583713 G 0.40 0.95 1.00 9340 32822729 0.043 0.006 1.6E-‐11 2 P rs762019 A 0.46 0.54 0.99 9340 32688601 0.042 0.006 1.6E-‐11 2 P rs2038534 A 0.38 0.86 1.00 9340 32659489 0.043 0.006 1.6E-‐11 2 P rs17011633 G 0.01 1.17 0.97 9340 32058673 -‐0.175 0.026 1.8E-‐11 2 P chr2:32531207:D C 0.40 0.76 0.98 9340 32531207 0.043 0.006 1.8E-‐11 2 P rs186763932 T 0.02 0.72 0.93 9340 31974014 -‐0.171 0.026 2.0E-‐11 2 P rs4952212 G 0.40 0.84 1.00 9340 32618493 -‐0.042 0.006 2.5E-‐11 2 P rs2254106 A 0.41 0.85 1.00 9340 32768797 0.042 0.006 2.7E-‐11 2 P rs1153121 A 0.39 0.82 0.99 9340 32524912 0.042 0.006 2.8E-‐11 2 P rs10172510 A 0.48 1.27 1.00 9340 32620888 -‐0.041 0.006 2.8E-‐11 2 P rs62136260 T 0.40 0.97 0.99 9340 32575447 -‐0.042 0.006 2.9E-‐11 2 P rs17011356 G 0.35 1.15 1.00 9340 31588577 0.043 0.006 3.1E-‐11 2 P rs13387204 C 0.35 1.21 1.00 9340 31589654 0.043 0.006 4.0E-‐11 2 P rs6729952 T 0.47 1.64 0.99 9340 32764922 0.041 0.006 4.3E-‐11 2 P rs7557451 T 0.10 0.16 0.95 9340 31936899 -‐0.070 0.011 4.6E-‐11 2 P rs62142410 C 0.11 0.40 0.87 9340 31963726 0.071 0.011 4.8E-‐11 2 P rs6718214 T 0.39 0.83 1.00 9340 32550485 -‐0.042 0.006 5.1E-‐11 2 P rs743163 C 0.35 1.21 1.00 9340 31589414 0.042 0.006 5.2E-‐11 2 P chr2:32636467:D D 0.40 0.82 0.97 9340 32636467 -‐0.042 0.006 5.3E-‐11 2 P rs2038537 T 0.50 0.89 1.00 9340 32545880 -‐0.040 0.006 6.1E-‐11 2 P rs3769600 A 0.48 1.31 1.00 9340 32616879 -‐0.040 0.006 6.2E-‐11 2 P rs2018410 C 0.35 1.24 1.00 9340 31594173 0.042 0.006 6.3E-‐11

40

2 P rs2281550 T 0.35 1.24 1.00 9340 31590759 0.042 0.006 7.5E-‐11 2 P rs3769597 T 0.47 0.88 0.99 9340 32691400 0.040 0.006 7.8E-‐11 2 P rs2281549 C 0.35 1.06 1.00 9340 31590626 0.042 0.006 9.2E-‐11 2 P rs62136267 T 0.15 0.61 0.85 9340 32592318 0.060 0.009 9.6E-‐11 2 P rs28412138 G 0.36 0.84 0.97 9340 31597930 0.042 0.007 1.0E-‐10 2 P rs151020518 C 0.01 0.53 0.89 9340 33062724 -‐0.204 0.032 1.2E-‐10 2 P rs62142414 A 0.13 0.52 0.88 9340 31975061 0.064 0.010 1.2E-‐10 2 P rs2281548 G 0.35 1.09 1.00 9340 31590545 0.042 0.006 1.2E-‐10 2 P rs62136336 G 0.45 1.24 0.92 9340 32804106 0.041 0.006 1.7E-‐10 2 P chr2:31650427:I D 0.31 0.73 0.81 9340 31650427 0.047 0.007 1.7E-‐10 2 P rs190030344 A 0.01 0.33 0.60 9340 32409783 -‐0.285 0.045 1.8E-‐10 2 P rs2710629 C 0.48 1.75 0.99 9340 32765844 0.039 0.006 1.9E-‐10 2 P rs190997810 A 0.01 0.54 0.89 9340 33079159 -‐0.201 0.032 2.0E-‐10 2 P rs12992095 A 0.25 2.48 1.00 9340 32661543 -‐0.045 0.007 2.0E-‐10 2 P rs62142413 G 0.19 0.45 0.90 9340 31974423 0.053 0.008 2.1E-‐10 2 P rs3769618 T 0.35 0.52 1.00 9340 31605447 0.041 0.006 2.1E-‐10 2 P rs114607281 G 0.01 0.00 0.70 9340 32358351 -‐0.198 0.031 2.2E-‐10 2 P rs2281547 C 0.37 0.64 1.00 9340 31598823 0.041 0.006 2.5E-‐10 2 P rs62136333 C 0.47 1.63 0.97 9340 32803874 0.040 0.006 2.6E-‐10 2 P rs4952089 T 0.40 1.62 0.99 9340 31599699 0.040 0.006 2.8E-‐10 2 P rs190616038 A 0.01 0.46 0.87 9340 32496877 -‐0.253 0.040 2.8E-‐10 2 P rs62142419 T 0.11 0.56 0.85 9340 32012730 0.068 0.011 2.9E-‐10 2 P rs6714633 G 0.39 0.03 0.88 9340 32859905 0.043 0.007 3.0E-‐10 2 P chr2:32685216:D T 0.39 0.16 0.92 9340 32685216 0.042 0.007 3.4E-‐10 2 P rs12995113 C 0.07 0.23 0.91 9340 32221763 -‐0.080 0.013 4.0E-‐10 2 P rs6543657 T 0.46 1.18 0.99 9340 32705085 0.039 0.006 4.5E-‐10 2 P rs186334657 A 0.01 0.42 0.88 9340 32789552 -‐0.241 0.039 5.3E-‐10 2 P rs76045936 T 0.02 1.38 0.93 9340 31656213 -‐0.158 0.026 7.5E-‐10

41

2 P rs188576618 A 0.01 0.34 0.87 9340 32495325 -‐0.226 0.037 1.0E-‐09 2 P rs186787482 T 0.01 0.42 0.89 9340 32501523 -‐0.233 0.038 1.1E-‐09 2 P rs149270271 C 0.02 0.49 0.96 9340 31853889 -‐0.150 0.025 1.5E-‐09 2 P rs6733396 A 0.41 0.31 0.98 9340 32663684 0.038 0.006 1.6E-‐09 2 P rs115216606 T 0.02 0.00 0.67 9340 31739338 -‐0.185 0.031 1.6E-‐09 2 P rs207401 C 0.42 1.96 0.99 9340 31597994 0.037 0.006 2.1E-‐09 2 P rs1864280 G 0.41 1.70 1.00 9340 31605615 0.037 0.006 2.2E-‐09 2 P chr2:32496224:D D 0.47 0.41 0.83 9340 32496224 -‐0.041 0.007 2.9E-‐09 2 P rs75331188 T 0.09 0.79 0.81 9340 32420110 0.073 0.012 3.2E-‐09 2 P rs6761566 A 0.01 0.00 0.95 9340 32480482 -‐0.217 0.037 3.2E-‐09 2 P rs12621192 T 0.32 0.75 1.00 9340 31588664 -‐0.039 0.007 3.7E-‐09 2 P rs79379878 C 0.07 0.26 0.92 9340 32152861 -‐0.074 0.013 4.0E-‐09 2 P chr2:31601541:D T 0.24 0.45 0.94 9340 31601541 0.044 0.008 4.0E-‐09 2 P rs6720163 G 0.42 1.80 1.00 9340 31605411 0.037 0.006 4.6E-‐09 2 P rs2070293 T 0.39 0.50 1.00 9340 31592895 -‐0.037 0.006 5.7E-‐09 2 P chr2:32832244:D C 0.46 1.68 0.88 9340 32832244 0.038 0.007 6.9E-‐09 2 P chr2:32690982:I D 0.29 1.99 0.97 9340 32690982 -‐0.040 0.007 8.3E-‐09 2 P rs2754514 A 0.43 0.78 0.98 9340 32788836 0.036 0.006 9.0E-‐09 2 P chr2:32611502:D G 0.45 1.70 0.94 9340 32611502 -‐0.037 0.006 9.3E-‐09 2 P rs182106637 T 0.01 0.38 0.93 9340 32372975 -‐0.212 0.037 1.1E-‐08 2 P rs6747560 T 0.42 1.15 0.92 9340 32784766 0.037 0.007 1.1E-‐08 2 P rs142215169 G 0.08 1.40 0.93 9340 31713362 0.066 0.012 1.1E-‐08 2 P rs192954772 T 0.00 0.00 0.89 9340 33000296 -‐0.277 0.049 1.2E-‐08 2 P rs206848 A 0.49 0.91 0.87 9340 31612719 0.038 0.007 1.3E-‐08 2 P rs182096440 G 0.01 0.41 0.95 9340 32107454 -‐0.212 0.037 1.5E-‐08 2 P chr2:32783389:I D 0.21 0.02 0.79 9340 32783389 0.049 0.009 1.5E-‐08 2 P rs184830458 A 0.01 0.41 0.94 9340 32061039 -‐0.211 0.037 1.6E-‐08 2 P rs149790092 A 0.01 0.39 0.94 9340 32387471 -‐0.209 0.037 1.7E-‐08

42

2 P rs56128492 A 0.21 0.58 0.97 9340 31857523 0.043 0.008 1.9E-‐08 2 P chr2:32832257:D T 0.47 0.78 0.93 9340 32832257 0.036 0.006 1.9E-‐08 2 P rs114467817 C 0.07 0.16 0.93 9340 32083640 -‐0.072 0.013 2.0E-‐08 2 P rs146041278 G 0.01 0.00 0.95 9340 32479650 -‐0.167 0.030 2.1E-‐08 2 P rs144601632 G 0.01 0.00 0.93 9340 32484935 -‐0.166 0.030 2.3E-‐08 2 P rs74522261 G 0.08 1.39 0.95 9340 31681479 0.065 0.012 2.4E-‐08 2 P rs190310798 T 0.01 0.40 0.95 9340 32309573 -‐0.206 0.037 2.6E-‐08 2 P rs71446025 T 0.07 0.13 0.94 9340 32084129 -‐0.072 0.013 2.7E-‐08 2 P rs71446057 T 0.07 0.17 0.85 9340 32414391 -‐0.076 0.014 2.8E-‐08 2 P rs74177012 G 0.27 1.69 0.98 9340 32638122 -‐0.039 0.007 3.0E-‐08 2 P rs2276592 G 0.29 1.81 1.00 9340 32667562 -‐0.038 0.007 3.1E-‐08 5 P rs17229943 C 0.06 0.46 0.70 9340 68682536 0.104 0.015 7.0E-‐12 5 P rs181170254 T 0.05 0.34 0.64 9340 68722409 0.103 0.018 6.4E-‐09 8 P rs2290414 A 0.45 0.65 0.98 9340 144643603 -‐0.051 0.006 2.8E-‐16 8 P rs13271361 A 0.46 0.75 0.98 9340 144650503 -‐0.050 0.006 9.5E-‐16 8 P rs1545536 T 0.22 0.45 0.98 9340 144643169 -‐0.060 0.008 1.1E-‐15 8 P rs13276307 T 0.25 0.88 0.98 9340 144646352 -‐0.057 0.007 4.7E-‐15 8 P rs13254352 A 0.25 1.31 0.98 9340 144649650 -‐0.055 0.007 5.9E-‐14 8 P rs56949579 A 0.40 0.37 0.96 9340 144646201 -‐0.041 0.006 2.1E-‐10 8 P rs3210186 G 0.41 1.71 0.97 9340 144682311 0.037 0.006 7.2E-‐09 8 P rs10099546 G 0.19 0.47 0.96 9340 144638734 0.046 0.008 1.2E-‐08 8 P rs12541647 C 0.15 0.81 1.00 9340 144647928 -‐0.049 0.009 1.6E-‐08 8 P rs1563148 C 0.41 1.53 1.00 9340 144664319 0.035 0.006 2.0E-‐08 8 P rs2123758 G 0.41 1.54 0.99 9340 144663661 0.036 0.006 2.0E-‐08 8 P rs4873808 T 0.17 1.73 0.98 9340 144693850 -‐0.047 0.008 2.8E-‐08 8 P rs1062391 G 0.41 1.52 1.00 9340 144662353 0.035 0.006 3.0E-‐08 8 P rs872935 G 0.41 1.67 0.99 9340 144658711 0.035 0.006 3.1E-‐08 11 P rs76154830 T 0.08 0.32 0.91 9340 112254971 -‐0.068 0.012 2.5E-‐08

43

11 P rs143951719 G 0.14 0.15 0.74 9340 105032773 0.058 0.010 2.0E-‐08 11 P rs17103763 A 0.25 0.62 1.00 9340 105003872 0.040 0.007 1.8E-‐08 11 P rs2017680 T 0.25 0.64 1.00 9340 105026002 0.040 0.007 1.8E-‐08 11 P rs1503403 C 0.25 0.68 1.00 9340 105030228 0.040 0.007 1.8E-‐08 11 P rs11226657 A 0.25 0.81 0.99 9340 105060775 0.041 0.007 1.7E-‐08 11 P rs12222898 C 0.25 0.60 1.00 9340 105013710 0.041 0.007 1.7E-‐08 11 P rs5002812 G 0.25 0.66 1.00 9340 105036178 0.041 0.007 1.7E-‐08 11 P rs4755096 T 0.25 0.99 0.99 9340 105060736 0.041 0.007 1.6E-‐08 11 P rs61891134 A 0.25 0.62 1.00 9340 105014902 0.041 0.007 1.5E-‐08 11 P rs11226647 C 0.25 0.69 0.99 9340 105040594 0.041 0.007 1.5E-‐08 11 P rs764078 A 0.25 0.87 0.98 9340 105056780 0.041 0.007 1.3E-‐08 11 P rs17490906 T 0.09 0.05 0.93 9340 112127526 0.064 0.011 1.2E-‐08 11 P rs57747660 C 0.25 0.90 1.00 9340 105052078 0.041 0.007 1.2E-‐08 11 P rs11226653 C 0.25 0.97 1.00 9340 105055825 0.041 0.007 1.2E-‐08 11 P rs7940485 C 0.25 0.94 1.00 9340 105053868 0.041 0.007 1.2E-‐08 11 P rs112491310 T 0.06 0.10 0.96 9340 112234130 -‐0.076 0.013 1.1E-‐08 11 P rs11226630 A 0.25 0.64 1.00 9340 105020562 0.041 0.007 1.1E-‐08 11 P rs4755086 G 0.25 0.64 1.00 9340 105021501 0.041 0.007 1.1E-‐08 11 P rs11226633 A 0.25 0.64 1.00 9340 105023044 0.041 0.007 1.1E-‐08 11 P rs1842893 C 0.25 0.64 1.00 9340 105023559 0.041 0.007 1.1E-‐08 11 P rs10891349 C 0.34 0.05 1.00 9340 112220382 0.038 0.007 7.9E-‐09 11 P rs67552207 A 0.34 0.07 1.00 9340 112220568 0.038 0.007 6.5E-‐09 11 P rs4937303 T 0.34 0.04 0.99 9340 112219865 0.038 0.007 6.4E-‐09 11 P rs11214175 A 0.34 0.09 0.98 9340 112216649 0.039 0.007 3.1E-‐09 11 P chr11:111993555:D C 0.11 0.23 0.71 9340 111993555 0.070 0.012 1.2E-‐09 11 P rs61902693 T 0.42 0.11 0.98 9340 112250980 -‐0.040 0.006 4.1E-‐10 11 P rs4323906 T 0.42 0.12 0.97 9340 112242860 -‐0.040 0.006 3.7E-‐10 11 P rs55741213 G 0.42 0.14 0.98 9340 112236075 -‐0.040 0.006 3.3E-‐10

44

11 P rs56113707 G 0.42 0.14 0.98 9340 112235975 -‐0.040 0.006 3.3E-‐10 11 P rs55772679 T 0.42 0.13 0.98 9340 112235908 -‐0.040 0.006 3.2E-‐10 11 P rs1534112 G 0.31 2.91 1.00 9340 112211791 0.042 0.007 2.0E-‐10 11 P rs4937291 G 0.31 2.87 1.00 9340 112211380 0.042 0.007 1.8E-‐10 11 P rs1534114 A 0.31 2.87 1.00 9340 112211026 0.042 0.007 1.8E-‐10 11 P rs1534115 G 0.31 2.87 1.00 9340 112210999 0.042 0.007 1.8E-‐10 11 P rs10891346 A 0.31 3.22 1.00 9340 112203992 0.043 0.007 1.6E-‐10 11 P rs873411 G 0.31 3.00 1.00 9340 112208482 0.043 0.007 1.6E-‐10 11 P rs10891348 G 0.31 2.75 0.99 9340 112212041 0.043 0.007 1.4E-‐10 11 P rs2103173 C 0.31 2.88 1.00 9340 112210052 0.043 0.007 1.4E-‐10 11 P rs1404792 T 0.31 3.04 1.00 9340 112208967 0.043 0.007 1.2E-‐10 11 P rs4269955 C 0.31 2.36 0.98 9340 112214091 0.043 0.007 1.2E-‐10 11 P rs113478665 A 0.07 0.13 0.84 9340 112118276 -‐0.088 0.014 1.1E-‐10 11 P rs5744267 C 0.05 0.84 0.85 9340 112018012 -‐0.100 0.015 4.7E-‐11 11 P rs141091241 T 0.03 0.12 0.75 9340 112111460 -‐0.131 0.020 3.1E-‐11 11 P rs113047286 C 0.06 0.09 0.81 9340 112049529 -‐0.103 0.014 3.2E-‐13 11 P chr11:112046568:D T 0.06 0.03 0.81 9340 112046568 -‐0.103 0.014 2.8E-‐13 11 P rs34273854 T 0.07 0.14 0.80 9340 112004797 -‐0.100 0.013 5.3E-‐14 11 P rs12419156 C 0.15 1.87 0.59 9340 111989862 -‐0.087 0.011 2.9E-‐14 11 P rs5744241 C 0.09 0.02 0.80 9340 112027144 -‐0.099 0.012 7.1E-‐16 11 P rs4937300 T 0.39 0.60 1.00 9340 112218097 -‐0.055 0.006 7.8E-‐18 11 P chr11:112205952:D T 0.39 0.22 0.96 9340 112205952 -‐0.056 0.006 5.6E-‐18 11 P rs10891325 G 0.34 1.70 0.95 9340 111996295 0.058 0.007 4.9E-‐18 11 P chr11:112205950:D T 0.36 0.19 0.92 9340 112205950 -‐0.058 0.007 3.8E-‐18 11 P rs10891326 A 0.34 1.75 0.95 9340 111996341 0.059 0.007 2.0E-‐18 11 P rs11821163 T 0.39 0.23 1.00 9340 112207502 -‐0.056 0.006 1.6E-‐18 11 P rs11825888 A 0.39 0.22 1.00 9340 112207339 -‐0.056 0.006 1.6E-‐18 11 P chr11:112208013:D T 0.39 0.22 1.00 9340 112208013 -‐0.056 0.006 1.5E-‐18

45

11 P rs4542449 C 0.39 0.21 1.00 9340 112209416 -‐0.056 0.006 1.4E-‐18 11 P chr11:112059195:D C 0.20 0.24 0.77 9340 112059195 0.078 0.009 9.7E-‐19 11 P rs1852138 G 0.43 0.04 0.98 9340 112201569 -‐0.061 0.006 6.6E-‐22 11 P rs2091289 G 0.39 0.22 0.98 9340 112187392 -‐0.064 0.006 2.4E-‐23 11 P rs11214093 T 0.44 1.68 1.00 9340 111992592 0.063 0.006 4.4E-‐24 11 P rs11214126 T 0.38 1.80 0.99 9340 112068219 -‐0.065 0.006 2.8E-‐24 11 P rs79919995 T 0.32 2.55 0.95 9340 112076967 0.071 0.007 3.5E-‐26 11 P rs10891328 T 0.33 0.96 0.99 9340 112009125 0.072 0.007 3.3E-‐28 11 P rs10891329 T 0.34 1.07 0.99 9340 112009892 0.072 0.007 2.5E-‐28 11 P rs77203424 A 0.17 0.34 0.93 9340 111994216 -‐0.095 0.009 2.3E-‐28 11 P rs4937100 G 0.34 1.52 0.99 9340 112013786 0.072 0.007 2.2E-‐28 11 P rs5744280 A 0.34 1.39 0.99 9340 112016514 0.073 0.007 2.0E-‐28 11 P rs5744240 A 0.34 1.65 1.00 9340 112027364 0.072 0.007 1.6E-‐28 11 P rs2115763 T 0.33 3.03 0.97 9340 112051169 0.074 0.007 3.1E-‐29 11 P rs10891341 C 0.34 2.36 0.98 9340 112073481 0.074 0.007 2.9E-‐29 11 P rs1972421 T 0.34 2.44 0.98 9340 112078120 0.074 0.007 2.9E-‐29 11 P chr11:112068269:I D 0.33 2.56 0.97 9340 112068269 0.074 0.007 2.9E-‐29 11 P rs4937123 G 0.33 2.72 0.98 9340 112043029 0.074 0.007 2.2E-‐29 11 P rs67245191 T 0.34 2.51 0.98 9340 112072161 0.074 0.007 2.0E-‐29 11 P rs4935984 A 0.34 2.51 0.98 9340 112072930 0.074 0.007 2.0E-‐29 11 P rs2564860 A 0.34 2.51 0.98 9340 112080132 0.074 0.007 1.7E-‐29 11 P rs2518356 G 0.34 2.51 0.98 9340 112082493 0.074 0.007 1.7E-‐29 11 P rs1896943 T 0.34 2.51 0.98 9340 112078974 0.074 0.007 1.6E-‐29 11 P rs10789863 T 0.33 2.46 0.98 9340 112077378 0.075 0.007 5.0E-‐30 11 P rs4937176 A 0.34 2.51 0.99 9340 112068973 0.075 0.007 4.1E-‐30 11 P rs7123686 C 0.34 2.54 0.99 9340 112065483 0.075 0.007 4.1E-‐30 11 P rs10891334 A 0.34 2.85 0.99 9340 112057100 0.074 0.007 4.0E-‐30 11 P rs11214124 T 0.34 2.48 0.99 9340 112061361 0.075 0.007 3.9E-‐30

46

11 P rs2059959 G 0.34 2.85 0.99 9340 112055979 0.074 0.007 3.7E-‐30 11 P rs7121458 A 0.34 2.82 0.99 9340 112055101 0.074 0.007 2.9E-‐30 11 P rs11214155 C 0.29 0.46 0.96 9340 112127930 -‐0.080 0.007 1.5E-‐30 11 P chr11:112041128:D T 0.34 3.42 0.98 9340 112041128 0.075 0.007 1.1E-‐30 11 P rs45569233 T 0.35 3.45 1.00 9340 112042071 0.075 0.006 2.7E-‐31 11 P rs13328843 C 0.35 3.37 1.00 9340 112044687 0.075 0.006 2.3E-‐31 11 P rs730879 G 0.35 3.38 1.00 9340 112040710 0.075 0.006 2.2E-‐31 11 P chr11:112049856:D G 0.34 3.31 0.98 9340 112049856 0.076 0.006 2.2E-‐31 11 P rs2904613 A 0.35 3.41 1.00 9340 112038086 0.075 0.006 1.9E-‐31 11 P rs35082717 G 0.28 0.33 0.97 9340 112110091 -‐0.082 0.007 1.5E-‐31 11 P rs2043055 G 0.36 2.42 1.00 9340 112031624 0.076 0.006 7.2E-‐33 11 P rs7106524 A 0.36 2.29 0.99 9340 112033636 0.077 0.006 2.3E-‐33 11 P chr11:112052729:D G 0.19 0.44 0.84 9340 112052729 -‐0.107 0.009 4.6E-‐36 11 P rs7116295 T 0.21 0.24 0.92 9340 111993398 -‐0.103 0.008 1.3E-‐38 11 P rs71478719 A 0.22 0.58 0.94 9340 111993847 -‐0.101 0.008 9.3E-‐39 11 P rs2250417 T 0.47 2.85 1.00 9340 112085316 -‐0.083 0.006 5.2E-‐41 11 P rs10891343 T 0.47 2.94 1.00 9340 112080384 -‐0.083 0.006 4.3E-‐41 11 P chr11:112078610:I D 0.28 1.65 0.96 9340 112078610 -‐0.096 0.007 2.0E-‐43 11 P chr11:112065981:D T 0.27 1.40 0.99 9340 112065981 -‐0.098 0.007 5.6E-‐45 11 P rs12795478 T 0.27 1.35 1.00 9340 112068100 -‐0.098 0.007 5.3E-‐45 11 P rs71466729 A 0.27 1.66 0.98 9340 112084109 -‐0.098 0.007 4.9E-‐45 11 P rs71478723 G 0.27 1.54 0.99 9340 112075085 -‐0.098 0.007 4.4E-‐45 11 P rs71478724 G 0.27 1.54 0.99 9340 112082775 -‐0.098 0.007 3.9E-‐45 11 P rs34389688 T 0.27 1.35 0.99 9340 112056400 -‐0.098 0.007 1.7E-‐45 11 P rs34006273 T 0.27 1.51 0.99 9340 112083096 -‐0.099 0.007 1.5E-‐45 11 P rs12420140 A 0.26 1.32 0.99 9340 112071294 -‐0.099 0.007 8.9E-‐46 11 P rs75649625 A 0.27 1.33 0.99 9340 112052194 -‐0.099 0.007 4.9E-‐46 11 P rs80011693 T 0.23 1.01 0.98 9340 112005483 -‐0.108 0.007 1.1E-‐47

47

11 P rs71478720 T 0.23 0.89 0.99 9340 112009605 -‐0.108 0.007 5.7E-‐49 11 P rs5744292 C 0.23 0.94 0.99 9340 112014136 -‐0.108 0.007 4.3E-‐49 11 P rs3882892 T 0.23 0.94 0.99 9340 112014986 -‐0.108 0.007 4.2E-‐49 11 P rs5744276 G 0.23 0.96 1.00 9340 112016871 -‐0.108 0.007 3.9E-‐49 11 P rs5744222 T 0.24 0.85 1.00 9340 112037014 -‐0.107 0.007 1.2E-‐49 11 P rs5744258 G 0.23 0.99 1.00 9340 112021767 -‐0.108 0.007 8.5E-‐50 11 P rs12420476 C 0.24 0.76 1.00 9340 112044398 -‐0.108 0.007 7.3E-‐50 11 P rs1834481 G 0.23 0.99 1.00 9340 112023827 -‐0.108 0.007 6.9E-‐50 11 P rs12797880 C 0.24 0.71 1.00 9340 112049191 -‐0.108 0.007 6.6E-‐50 11 P rs4988359 C 0.23 0.99 1.00 9340 112025915 -‐0.108 0.007 6.5E-‐50 11 P rs7121554 T 0.24 0.71 1.00 9340 112048051 -‐0.108 0.007 6.1E-‐50 11 P rs7131094 T 0.24 0.71 1.00 9340 112044917 -‐0.108 0.007 5.8E-‐50 11 P rs5744256 G 0.23 0.99 1.00 9340 112022848 -‐0.108 0.007 5.0E-‐50 11 P rs5744249 C 0.23 0.98 1.00 9340 112025306 -‐0.108 0.007 4.9E-‐50 11 P rs11606049 T 0.23 1.05 0.99 9340 112033129 -‐0.108 0.007 4.0E-‐50 11 P rs12796114 C 0.24 0.67 1.00 9340 112049140 -‐0.108 0.007 2.1E-‐50 11 P rs36077191 T 0.24 0.65 1.00 9340 112039421 -‐0.108 0.007 1.9E-‐50 11 P chr11:112034062:I TA 0.23 0.96 1.00 9340 112034062 -‐0.109 0.007 1.2E-‐50 11 P rs11226630 A 0.25 0.64 1.00 9340 105020562 0.041 0.007 1.1E-‐08 11 P rs11226633 A 0.25 0.64 1.00 9340 105023044 0.041 0.007 1.1E-‐08 11 P rs1842893 C 0.25 0.64 1.00 9340 105023559 0.041 0.007 1.1E-‐08 11 P rs4755086 G 0.25 0.64 1.00 9340 105021501 0.041 0.007 1.1E-‐08 11 P rs7940485 C 0.25 0.94 1.00 9340 105053868 0.041 0.007 1.2E-‐08 11 P rs11226653 C 0.25 0.97 1.00 9340 105055825 0.041 0.007 1.2E-‐08 11 P rs57747660 C 0.25 0.90 1.00 9340 105052078 0.041 0.007 1.2E-‐08 11 P rs764078 A 0.25 0.87 0.98 9340 105056780 0.041 0.007 1.3E-‐08 11 P rs11226647 C 0.25 0.69 0.99 9340 105040594 0.041 0.007 1.5E-‐08 11 P rs61891134 A 0.25 0.62 1.00 9340 105014902 0.041 0.007 1.5E-‐08

48

11 P rs4755096 T 0.25 0.99 0.99 9340 105060736 0.041 0.007 1.6E-‐08 11 P rs5002812 G 0.25 0.66 1.00 9340 105036178 0.041 0.007 1.7E-‐08 11 P rs12222898 C 0.25 0.60 1.00 9340 105013710 0.041 0.007 1.7E-‐08 11 P rs11226657 A 0.25 0.81 0.99 9340 105060775 0.041 0.007 1.7E-‐08 11 P rs1503403 C 0.25 0.68 1.00 9340 105030228 0.040 0.007 1.8E-‐08 11 P rs2017680 T 0.25 0.64 1.00 9340 105026002 0.040 0.007 1.8E-‐08 11 P rs17103763 A 0.25 0.62 1.00 9340 105003872 0.040 0.007 1.8E-‐08 11 P rs143951719 G 0.14 0.15 0.74 9340 105032773 0.058 0.010 2.0E-‐08 2 C rs189402358 A 0.00 0.00 0.94 9340 32269307 -‐0.415 0.055 4.4E-‐14 2 C rs74494678 C 0.02 0.13 0.95 9340 32332009 -‐0.137 0.025 2.7E-‐08 2 C rs193161863 C 0.01 0.00 0.73 9340 32336489 -‐0.237 0.041 4.6E-‐09 2 C chr2:32341309 G 0.00 0.00 0.98 9340 32341309 -‐0.395 0.052 4.6E-‐14 2 C rs2294177 A 0.02 0.13 0.92 9340 32353323 -‐0.146 0.025 8.7E-‐09 2 C rs112067196 G 0.00 0.00 0.94 9340 32360852 -‐0.360 0.048 9.5E-‐14 2 C rs141408916 C 0.01 0.00 0.84 9340 32388578 -‐0.342 0.046 7.8E-‐14 2 C rs190030344 A 0.01 0.33 0.60 9340 32409783 -‐0.254 0.044 5.1E-‐09 2 C rs191543843 A 0.00 0.00 0.98 9340 32426321 -‐0.393 0.052 4.6E-‐14 2 C exm184959 A 0.00 0.00 0.99 9340 32463365 -‐0.397 0.049 3.8E-‐16 11 C rs79919995 T 0.32 2.55 0.95 9340 112076967 0.039 0.007 4.3E-‐08 11 C rs4463877 C 0.39 0.28 0.99 9340 112055356 0.038 0.007 2.5E-‐08 11 C rs12796145 C 0.25 0.14 0.99 9340 112076587 -‐0.042 0.007 1.4E-‐08 11 C chr11:112071880:D A 0.27 0.11 0.94 9340 112071880 -‐0.043 0.007 9.8E-‐09 11 C rs2115763 T 0.33 3.03 0.97 9340 112051169 0.042 0.007 2.0E-‐09 11 C rs4937123 G 0.33 2.72 0.98 9340 112043029 0.042 0.007 1.8E-‐09 11 C rs5744280 A 0.34 1.39 0.99 9340 112016514 0.042 0.007 1.6E-‐09 11 C rs5744240 A 0.34 1.65 1.00 9340 112027364 0.042 0.007 1.5E-‐09 11 C rs4937100 G 0.34 1.52 0.99 9340 112013786 0.042 0.007 1.5E-‐09 11 C rs10891328 T 0.33 0.96 0.99 9340 112009125 0.042 0.007 1.4E-‐09

49

11 C rs575159 T 0.31 0.58 0.96 9340 112001886 -‐0.043 0.007 1.3E-‐09 11 C rs10891329 T 0.34 1.07 0.99 9340 112009892 0.042 0.007 1.3E-‐09 11 C rs4937113 A 0.43 0.01 1.00 9340 112029721 0.042 0.007 1.0E-‐09 11 C rs11214138 C 0.25 0.11 0.98 9340 112084061 -‐0.045 0.007 1.0E-‐09 11 C rs10891341 C 0.34 2.36 0.98 9340 112073481 0.043 0.007 9.1E-‐10 11 C rs11214134 C 0.26 0.08 0.99 9340 112080424 -‐0.045 0.007 8.1E-‐10 11 C rs11214135 C 0.26 0.08 0.99 9340 112081208 -‐0.045 0.007 8.1E-‐10 11 C rs3882891 G 0.43 0.05 1.00 9340 112014761 0.043 0.007 7.4E-‐10 11 C rs4935984 A 0.34 2.51 0.98 9340 112072930 0.043 0.007 7.2E-‐10 11 C rs67245191 T 0.34 2.51 0.98 9340 112072161 0.043 0.007 7.2E-‐10 11 C chr11:112065742:D T 0.23 0.11 0.93 9340 112065742 -‐0.049 0.008 7.1E-‐10 11 C rs2564860 A 0.34 2.51 0.98 9340 112080132 0.043 0.007 6.9E-‐10 11 C rs1972421 T 0.34 2.44 0.98 9340 112078120 0.043 0.007 6.9E-‐10 11 C rs2518356 G 0.34 2.51 0.98 9340 112082493 0.043 0.007 6.8E-‐10 11 C chr11:112065737:D G 0.23 0.12 0.93 9340 112065737 -‐0.049 0.008 6.8E-‐10 11 C rs10891339 A 0.26 0.02 1.00 9340 112070174 -‐0.045 0.007 6.7E-‐10 11 C rs11214128 A 0.26 0.02 1.00 9340 112068758 -‐0.045 0.007 6.7E-‐10 11 C rs549908 G 0.31 0.30 1.00 9340 112020916 -‐0.044 0.007 6.7E-‐10 11 C rs1896943 T 0.34 2.51 0.98 9340 112078974 0.043 0.007 6.4E-‐10 11 C rs795470 A 0.31 0.48 0.99 9340 112005820 -‐0.044 0.007 6.3E-‐10 11 C rs11214127 A 0.25 0.02 1.00 9340 112068593 -‐0.045 0.007 5.8E-‐10 11 C rs360720 G 0.31 0.28 1.00 9340 112021944 -‐0.044 0.007 5.8E-‐10 11 C rs360721 C 0.31 0.27 1.00 9340 112025916 -‐0.044 0.007 5.5E-‐10 11 C rs10891337 T 0.26 0.03 1.00 9340 112063254 -‐0.045 0.007 5.4E-‐10 11 C rs11214120 C 0.26 0.03 1.00 9340 112059715 -‐0.045 0.007 5.4E-‐10 11 C rs56475786 A 0.26 0.03 1.00 9340 112058408 -‐0.045 0.007 5.4E-‐10 11 C rs10891335 T 0.26 0.03 1.00 9340 112059277 -‐0.045 0.007 5.4E-‐10 11 C rs360729 T 0.31 0.32 1.00 9340 112016921 -‐0.044 0.007 5.3E-‐10

50

11 C rs472997 T 0.31 0.34 1.00 9340 112011772 -‐0.044 0.007 5.3E-‐10 11 C rs10891330 A 0.31 0.36 1.00 9340 112011167 -‐0.044 0.007 5.3E-‐10 11 C rs12283162 G 0.26 0.02 0.99 9340 112057306 -‐0.046 0.007 5.2E-‐10 11 C rs1946518 T 0.41 0.22 1.00 9340 112035458 0.043 0.007 5.0E-‐10 11 C rs545622 A 0.31 0.49 1.00 9340 112008793 -‐0.044 0.007 5.0E-‐10 11 C rs1946519 A 0.41 0.22 1.00 9340 112035507 0.043 0.007 5.0E-‐10 11 C chr11:112065743:D C 0.23 0.06 0.94 9340 112065743 -‐0.049 0.008 4.7E-‐10 11 C rs10891336 A 0.25 0.03 0.99 9340 112061441 -‐0.046 0.007 4.4E-‐10 11 C rs243908 G 0.31 0.50 1.00 9340 112005939 -‐0.044 0.007 4.1E-‐10 11 C rs636854 A 0.31 0.52 1.00 9340 112008295 -‐0.044 0.007 4.0E-‐10 11 C rs10789863 T 0.33 2.46 0.98 9340 112077378 0.044 0.007 3.6E-‐10 11 C rs168627 T 0.31 0.47 1.00 9340 112005681 -‐0.044 0.007 3.4E-‐10 11 C rs10891334 A 0.34 2.85 0.99 9340 112057100 0.043 0.007 3.0E-‐10 11 C chr11:112068269:I D 0.33 2.56 0.97 9340 112068269 0.044 0.007 2.9E-‐10 11 C rs2059959 G 0.34 2.85 0.99 9340 112055979 0.044 0.007 2.9E-‐10 11 C chr11:112041128:D T 0.34 3.42 0.98 9340 112041128 0.044 0.007 2.9E-‐10 11 C rs7121458 A 0.34 2.82 0.99 9340 112055101 0.044 0.007 2.8E-‐10 11 C rs7123686 C 0.34 2.54 0.99 9340 112065483 0.044 0.007 2.8E-‐10 11 C rs4937176 A 0.34 2.51 0.99 9340 112068973 0.044 0.007 2.8E-‐10 11 C rs11214124 T 0.34 2.48 0.99 9340 112061361 0.044 0.007 2.8E-‐10 11 C rs360730 C 0.30 0.42 0.98 9340 112017648 -‐0.045 0.007 2.8E-‐10 11 C rs360712 G 0.26 0.36 1.00 9340 112040027 -‐0.046 0.007 2.0E-‐10 11 C rs45569233 T 0.35 3.45 1.00 9340 112042071 0.044 0.007 1.8E-‐10 11 C rs13328843 C 0.35 3.37 1.00 9340 112044687 0.044 0.007 1.7E-‐10 11 C rs730879 G 0.35 3.38 1.00 9340 112040710 0.044 0.007 1.7E-‐10 11 C rs2904613 A 0.35 3.41 1.00 9340 112038086 0.044 0.007 1.5E-‐10 11 C chr11:112049856:D G 0.34 3.31 0.98 9340 112049856 0.045 0.007 1.0E-‐10 11 C rs2043055 G 0.36 2.42 1.00 9340 112031624 0.045 0.007 3.2E-‐11

51

11 C rs7106524 A 0.36 2.29 0.99 9340 112033636 0.046 0.007 1.7E-‐11 11 C rs10891343 T 0.47 2.94 1.00 9340 112080384 -‐0.048 0.007 1.7E-‐11 11 C rs2250417 T 0.47 2.85 1.00 9340 112085316 -‐0.048 0.007 1.4E-‐11 11 C rs11214105 A 0.28 0.23 1.00 9340 112037653 -‐0.050 0.007 3.4E-‐12 11 C rs795468 T 0.28 0.33 1.00 9340 112042197 -‐0.050 0.007 3.0E-‐12 11 C rs360717 A 0.28 0.22 1.00 9340 112034725 -‐0.050 0.007 2.8E-‐12 11 C rs795467 A 0.28 0.03 1.00 9340 112031080 -‐0.050 0.007 2.6E-‐12 11 C rs1290349 A 0.28 0.23 1.00 9340 112037554 -‐0.050 0.007 2.5E-‐12 11 C rs189667 G 0.28 0.04 1.00 9340 112033604 -‐0.050 0.007 2.5E-‐12 11 C rs360719 G 0.28 0.22 1.00 9340 112036149 -‐0.050 0.007 2.4E-‐12 11 C rs187238 G 0.28 0.21 1.00 9340 112034988 -‐0.050 0.007 2.3E-‐12 11 C rs360715 T 0.28 0.00 1.00 9340 112032249 -‐0.050 0.007 2.2E-‐12 11 C rs11214112 T 0.28 0.33 1.00 9340 112047456 -‐0.051 0.007 2.0E-‐12 11 C rs1293344 G 0.28 0.26 1.00 9340 112037384 -‐0.051 0.007 1.9E-‐12 11 C rs360718 C 0.28 0.23 1.00 9340 112034739 -‐0.051 0.007 1.7E-‐12 11 C rs11214115 T 0.28 0.31 0.99 9340 112050326 -‐0.051 0.007 1.7E-‐12 * P – primary analyses, C – conditional analyses † Allele D = deletion ‡ -‐log10(HWE P-‐value)

52

Table S8. Sensitivity analyses for the top SNPs by stratifying individuals based on geographic origin.

All

European (N=9195)

African (N=53)

Asian (N=78)

Beta SE beta P-‐value Beta SE beta P-‐value Beta SE beta P-‐value Beta SE beta P-‐value Treatment (clopidogrel) -‐0.001 0.008 9.2E-‐01 0.000 0.009 9.7E-‐01 -‐0.075 0.162 6.5E-‐01 -‐0.008 0.099 9.4E-‐01 Sex (male) 0.121 0.009 2.0E-‐38 0.121 0.009 7.3E-‐38 -‐0.017 0.194 9.3E-‐01 0.153 0.126 2.3E-‐01 pc1 0.024 0.071 7.4E-‐01 -‐0.028 0.137 8.4E-‐01 -‐0.037 1.601 9.8E-‐01 0.369 1.517 8.1E-‐01 pc2 0.093 0.112 4.1E-‐01 0.147 0.201 4.6E-‐01 1.371 3.465 7.0E-‐01 -‐2.663 2.257 2.4E-‐01 pc3 -‐0.818 0.128 1.5E-‐10 -‐0.742 0.288 9.9E-‐03 -‐0.766 3.016 8.0E-‐01 3.651 5.936 5.4E-‐01 pc4 0.650 0.151 1.7E-‐05 0.641 0.152 2.4E-‐05 1.784 3.357 6.0E-‐01 3.135 2.115 1.4E-‐01 AGE -‐0.0007 0.0004 9.1E-‐02 -‐0.0008 0.0004 4.2E-‐02 0.0117 0.0104 2.7E-‐01 0.0083 0.0048 8.5E-‐02 BMI 0.0081 0.0010 1.7E-‐17 0.0081 0.0010 3.7E-‐17 -‐0.0043 0.0146 7.7E-‐01 0.0081 0.0154 6.0E-‐01 MHDMFL* (yes) 0.063 0.010 1.5E-‐09 0.067 0.011 2.2E-‐10 0.107 0.201 6.0E-‐01 -‐0.109 0.111 3.3E-‐01 PAD† (yes) 0.077 0.017 5.0E-‐06 0.075 0.017 1.1E-‐05 0.536 0.429 2.2E-‐01 0.404 0.273 1.5E-‐01 CRENDIS‡ (yes) 0.116 0.023 3.4E-‐07 0.113 0.023 8.3E-‐07 -‐0.047 0.366 9.0E-‐01 0.281 0.269 3.0E-‐01 LLARDFL§ (yes) -‐0.034 0.011 1.7E-‐03 -‐0.032 0.011 3.0E-‐03 -‐0.399 0.236 1.0E-‐01 0.031 0.118 8.0E-‐01 rs385076 0.109 0.006 1.5E-‐70 0.109 0.006 3.0E-‐69 0.209 0.207 3.2E-‐01 0.202 0.089 2.7E-‐02 exm184959 -‐0.407 0.048 3.2E-‐17 -‐0.402 0.049 1.2E-‐16 -‐0.782 0.667 2.5E-‐01 NA NA NA chr11.112034062 -‐0.128 0.008 1.3E-‐64 -‐0.127 0.008 1.4E-‐63 -‐0.357 0.255 1.7E-‐01 -‐0.164 0.216 4.5E-‐01 rs360718 -‐0.051 0.007 1.2E-‐12 -‐0.050 0.007 2.4E-‐12 -‐0.088 0.151 5.6E-‐01 -‐0.036 0.106 7.3E-‐01 rs17229943 0.102 0.015 2.7E-‐12 0.103 0.015 1.7E-‐12 -‐0.065 0.652 9.2E-‐01 0.009 0.229 9.7E-‐01 rs2290414 -‐0.052 0.006 1.7E-‐17 -‐0.051 0.006 5.5E-‐17 0.053 0.132 6.9E-‐01 -‐0.078 0.078 3.2E-‐01 rs11226633 0.041 0.007 3.7E-‐09 0.041 0.007 4.8E-‐09 -‐0.015 0.161 9.2E-‐01 0.003 0.076 9.6E-‐01 *MHDMFL -‐ Medical history of diabetes mellitus †PAD -‐ History of peripheral arterial disease ‡CRENDIS -‐ History of chronic renal disease §LLARDFL -‐ Lipid lowering agent on day of randomization

53

Figure S1. Principal component plot of the pooled dataset (estimated from overlapping genotyped markers only). A) PC plot of the first two principal components. Clustering

of individuals into six clusters using the four first genetic principal components (k-‐means clustering with the Hartigan and Wong method) are shown as different symbols in

the figure. B) Parallel co-‐ordinates plot for the first four principal components for the six clusters. C) Scree plot for the first ten principal components.

0

0.0005

0.001

0.0015

0.002

0 1 2 3 4 5 6 7 8 9 10

Varia

nces

PCs

55

Figure S2. Detailed view of the IL18 region and the most significant SNPs that were associated with IL-‐18 levels in the primary pooled analyses (in red), and the

conditional analyses (in purple). In A) the whole region showing all the most significant SNPs are displayed and in B) the region around the IL18 promoter is

zoomed in. The figure also shows the genes in the regions (RefSeq Genes) and transcription factor binding (Transcription Factor ChIP-‐seq from ENCODE) in

different cell types: 1 (H1-‐hESC), G (GM12878), H (HeLa-‐S3), K (K562, K562b), L (HepG2, HepG2b), U (HUVEC), a (A549, AG04449, AG09309, AG09319, AG10803,

AoAF), b (BJ), c (Caco-‐2), e (ECC-‐1), f (Fibrobl), g (GM06990, GM10847, GM12864, GM12865, GM12872, GM12873, GM12874, GM12875, GM12891, GM12892,

GM15510, GM18505, GM18526, GM18951,, GM19099, GM19193, Gliobla), h (HBMEC, HCPEpiC, HCT-‐116, HEEpiC, HEK293, HEK293(b), HMEC, HMF, HPAF, HPF,

HRE, HSMM, HSMMtube, HTB-‐11), k (K562), m (MCF-‐7, MCF10A-‐Er-‐Src), n (NB4, NH-‐A, NHDF-‐Ad, NHEK, NHLF, NT2-‐D1), o (Osteobl), p (PANC-‐1, PBDE, PFSK-‐1,

ProgFib), r (Raji), s (SAEC, SH-‐SY5Y, SK-‐N-‐SH_RA), t (T-‐47D, T-‐REx-‐HEK293), u (U2OS), w (WERI-‐Rb-‐1), and y (U87). The bottom of the figures shows the predicted

chromatin state (Chromatin State Segmentation by HMM from ENCODE/Broad) in GM12878 (B-‐lymphocyte, lymphoblastoid, International HapMap Project -‐

CEPH/Utah -‐ European Caucasion, Epstein-‐Barr Virus), H1-‐hESC (embryonic stem cells), HepG2 (hepatocellular carcinoma), HMEC (mammary epithelial cells),

HSMM (skeletal muscle myoblasts), HUVEC (umbilical vein endothelial cells) K562 (leukemia), NHEK (epidermal keratinocytes), and NHLF (lung fibroblasts). The

explanation to the color-‐coding for the chromatin states is inserted as a box in the figure.

56

Figure S3. Detailed view of the NLRC region and the most significant SNPs that were associated with IL-‐18 levels in the primary pooled analyses (in red). In A) the

whole region showing all the most significant SNPs are displayed and in B) the region around the NLRC promoter, where the most significant SNP is located, is

zoomed in. The figure also shows the genes in the regions and transcription factor binding. The bottom of the figures shows the predicted chromatin state. For more

explanations of the figure please see legends to Figure S2.

57

Figure S4. Detailed view of the MROH6 region on chromosome 8 and the most significant SNPs that were associated with IL-‐18 levels in the primary pooled

analyses (in red). The figure also shows the genes in the regions and transcription factor binding. The bottom of the figures shows the predicted chromatin state.

For more explanations of the figure please see legends to Figure S2.

58

Figure S5. Detailed view of the CARD16-‐18 and CASP-‐region and the most significant SNPs that were associated with IL-‐18 levels in the primary pooled analyses (in

red). In A) the whole region showing all the most significant SNPs are displayed and in B) the region around CARD18, where all SNPs are located is enlarged. The

figure also shows the genes in the regions and transcription factor binding. The bottom of the figures shows the predicted chromatin state. For more explanations

of the figure please see legends to Figure S2

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Figure S6. Q–Q plot for the GWAS of the combined data (discovery + replication cohort)

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