Summaries of oral sessions at the XXI World Congress of Psychiatric Genetics, Boston, Massachusetts,...

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Summaries of oral sessions at the XXI World Congress ofPsychiatric Genetics, Boston, Massachusetts, 17–21 October2013: state of the fieldHilary Akpudoa, Branko Aleksicg, Anna Alkelaih, Christie Burtonf,Tania Carillo Roai, David T.W. Chenb, Min-Chih Chengl, Enrico Cocchin,Lea K. Davisc, Isabele G. Giorio, Leon M. Hubbardp, Alison Merikangass,Nagaraj S. Moilyt, Adeniran Okewoleu, Emily Olfsond, Irene Pappav,w,x,Markus Reittj, Ajeet B. Singhz, Julia Steinbergq, Jana Strohmaierk, Te-Tien Tingm,Kimm J.E. van Hulzeny, Anne O’Sheae and Lynn E. DeLisie

The XXI World Congress of Psychiatric Genetics (WCPG),sponsored by the International Society of PsychiatricGenetics (ISPG), took place in Boston, Massachusetts, on17–21 October 2013. Approximately 900 participantsgathered to discuss the latest findings in this rapidlyadvancing field. The following report was written by studenttravel awardees. Each was assigned one or more sessionsas a rapporteur. This manuscript represents topics coveredin most, but not all of the oral presentations during theconference, and contains some of the major notable newfindings reported. Psychiatr Genet 00:000–000 © 2014Wolters Kluwer Health | Lippincott Williams & Wilkins.

Psychiatric Genetics 2014, 00:000–000

Keywords: commercial DNA testing, DNA,International Society of Psychiatric Genetics, post-traumatic stress disorder,schizophrenia, sequencing, substance abuse,World Congress of Psychiatric Genetics

aMeharry Medical College, Nashville, Tennessee, bHuman Genetics Branch,National Institute of Mental Health, National Institutes of Health, Bethesda,Maryland, cSection of Genetic Medicine, Department of Medicine, University ofChicago, Chicago, Illinois, dWashington University School of Medicine atWashington University Medical Center, St Louis, Missouri, eHarvard MedicalSchool, VA Boston Healthcare System, Brockton, Massachusetts, fHospital forSick Children, Toronto, Ontario, USA, gDepartment of Psychiatry, Nagoya

University Graduate School of Medicine, Nagoya, Japan, hThe Weizmann Instituteof Science, Rehovot, Israel, iMax-Planck Institute of Psychiatry, Munich, jSectionon Psychiatric Genetics, University Medical Center, University of Goettingen,Goettingen, kDepartment of Genetic Epidemiology in Psychiatry, Central Instituteof Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg,Germany, lDepartment of Psychiatry, Yuli Mental Health Research Center, YuliBranch, Taipei Veterans General Hospital, Yuli, mInstitute of Epidemiology andPreventive Medicine, College of Public Health, National Taiwan University, Taipei,Taiwan, nInstitute of Psychiatry, Department of Biomedical and NeuromotorScience – DIBINEM, University of Bologna, Bologna, Italy, oDepartment ofGeneral Biology, Fluminense Federal University, Rio de Janeiro, Brazil, pMRCCentre for Neuropsychiatric Genetics and Genomic, Institute of PsychologicalMedicine and Clinical Neurosciences, Cardiff University, Cardiff, qMedicalResearch Council Functional Genomics Unit, Department of Physiology, Anatomy,and Genetics, rThe Wellcome Trust Centre for Human Genetics, University ofOxford, Oxford, UK, sDepartment of Psychiatry and Neuropsychiatric GeneticsResearch Group, Trinity College Dublin, Trinity Centre for Health Sciences, StJames’s Hospital, Dublin, Ireland, tNeurosciences, Molecular Genetics Laboratory,Neurobiology Research Center, National Institute of Mental Health andNeurosciences, uNeuropsychiatric Hospital, Abeokuta, Nigeria, vSchool ofPedagogical and Educational Sciences, Erasmus University, wThe Generation RStudy Group, Erasmus University Medical Center, xDepartment of Child andAdolescent Psychiatry/Psychology, Erasmus University Medical Center-SophiaChildren’s Hospital, Rotterdam, yDepartment of Human Genetics, RadboudUniversity Medical Centre, Nijmegen, The Netherlands and zSchool of Medicine,Deakin University, Victoria, Australia

Correspondence to Lynn E. DeLisi, MD, Harvard Medical School, Brockton VABoston Healthcare System, 940 Belmont Street, Brockton, MA 02301, USATel: + 1 774 826 3155; fax: + 1 774 826 1758; e-mail: [email protected]

Received 13 February 2014 Accepted 20 April 2014

IntroductionThe International Society of Psychiatric Genetics (ISPG)

was first established as a nonprofit corporation in the USA

in 1992 and is now a worldwide organization that strives

for the highest standards in the application of genetic

methodologies to the study of psychiatric disorders. It

was formed to provide a stable structure for continual

congresses in this field with the mission of overseeing an

annual gathering at different international locations. The

2013 World Congress of Psychiatric Genetics (WCPG),

sponsored by the ISPG, took place on 17–21 October

2013 in Boston. Over 900 researchers in psychiatry, psy-

chology, and molecular genetics participated. The con-

gress was co-chaired by Harvard professors, Drs Jordan

Smoller and Lynn DeLisi. Rapporteurs for these sessions

were student travel awardees. Their tasks were to sum-

marize individual sessions as well as relevant discussions.

Similar accounts of the 2007, 2008, 2009, 2010, 2011, and

2012 congresses held in New York City, Osaka, Japan,

San Diego, California, Athens, Greece, and Washington,

DC, and Hamburg, Germany, have been published

previously (Alkelai et al., 2008; Bergen et al., 2009, 2011;Amstadter et al., 2010; Dai et al., 2012; Anderson-Schmidt

et al., 2013).

The following report represents the topics and major

findings of the year covered during most oral sessions and

Rapporteurs in alphabetical order, all performed equal work.

Anne O’Shea and Lynn E. DeLisi are the coordinators of rapporteurs and thisreport and also the editors of this report.

Review article 1

0955-8829 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YPG.0000000000000043

mailto:[email protected]


they appear together under major topics, irrespective of

the timing or the format of specific sessions. During this

congress, the most obvious theme was the necessity for

large international collaborations as the way forward to

unravel the genetic architecture of mental illness and that

the outcome may be the defining of a new diagnostic

system.

Changing the DSM through genetics (reportedby Ajeet B. Singh)The theme of this 2013 congress was ‘Defining Mental

Illness through Genetics’ and was discussed in an

opening plenary session chaired by Dr Steven Hyman

(Harvard University and Broad Institute, former Director

of NIMH, USA). Presentations from a panel of experts

included Drs Kenneth Kendler (Virginia, USA), Myrna

Weissman (Columbia, New York, USA), Jan Buitelaar

(Nijmegen, the Netherlands), Michael Owens (Cardiff,

UK), and Cuthbert (NIMH, USA). Tensions between

dimensional and categorical nosologies, pleiotropy, and

polygenetic inheritance, stochastic and deterministic

mechanisms, and an environmental epigenetically medi-

ated neurodevelopmental overlay yielded a thought-

provoking session.

Dr Hyman quoted Robins and Guze (1970) ‘Reliable and

valid diagnosis would follow from – clinical description,

laboratory studies, delineation of one disorder from

another, follow-up studies, family studies’, but then

reflected that ‘clinically diagnosis transgresses bound-

aries’ and the DSM (Diagnostic & Statistical Manual) wasakin to an ‘automobile pile-up: several hundred disorders

with arbitrary thresholds’. Comorbidity was common in

part because of the ‘desire to achieve homogeneity so

categories are over specified’ and conveniently ‘those

that don’t fit in get the label, NOS (Not Otherwise

Specified)’. He went on to state that the DSM is ‘easy to

make fun of, hard to do better – there is no bright line to

define categories’. He concluded that it is ‘not clear how

much genetics itself will contribute to diagnosis’, but

believed that ‘dimensions permit empirical data to

influence diagnostic thresholds’.

Dr Kendler postulated six phases of how psychiatric

nosology and genetics have interacted historically. ‘Phase

1, an ancillary source of diagnostic information; Phase 2,

family history as a formal validator of a proposed diag-

nosis (Robins and Guze, 1970); Phase 3, multivariate

models; Phase 4, candidate genes; Phase 5, GWAS and

patterns of SNPs; Phase 6, polygene scores’. He reflected

on early work examining the influence of family history

on the prognosis of schizophrenia (Fowler et al., 1972),and elegantly articulated the problems of multivariate

models ‘If mood disorders are mammals and anxiety

disorders are fish is GAD (Generalized Anxiety Disorder)

a dolphin?’ He went on to lament the ‘nosological castles

on sand from small variance findings’ stemming from

candidate gene studies evolving into the ‘complex mix…

spectrum of genes’ identified in genome-wide association

studies (GWAS). He concluded by positing that the next

phase will be polygene scores that indicate diagnostic

likelihood, citing the work of Naomi Wray and colleagues

indicating overlapping genetics of psychiatric illnesses

and stochastic heredity (Lee et al., 2013). He concluded

‘What do nosologists want from genetics? This, depends

on the model of psychiatric diagnosis. If we want syn-

dromal, descriptive diagnoses, such as with the DSM,

then nosologists want aggregate data, the broad picture

(heritability/polygene scores). But, if we move towards

more etiologically based diagnoses, then the picture

shifts considerably. The results obtained at single var-

iants and aggregates of genetic variants, and probably

associated network analysis, will ultimately prove more

useful’.

Dr Weissman provided an epidemiological perspective

‘large representative samples may generate new pheno-

types, endophenotypes independent of disease.

Hypotheses regarding environmental exposure can be

generated’. ‘The hottest area is epigenetics’ and envir-

onmental factors (including in-utero exposure) could be

important by modifying the epigenetic imprint.

Dr Buitelaar suggested that ‘genetics will probably not

deliver defining of diagnosis’. Increasing recognition of

the role of de-novo mutations and data indicating ‘hun-

dreds of common variants with very small effect size

appear to play a role’, underscoring his view. He raised

the importance of ‘reconceptualized psychiatry as disease

of not just brain but also body’ with pleiotropy between

somatic and mental illnesses. The promise of genetics is

that it ‘can delineate underlying mechanisms and more

homogeneous subgroups’, helping us ‘deconstruct dis-

orders’, potentially yielding novel preventative and

therapeutic approaches.

Dr Owens emphasized a ‘gradient of neurodevelop-

mental pathology’, with damaging mutations more often

seen in intellectual disability than autism spectrum dis-

orders (ASDs) or schizophrenia, ‘supporting a gradient of

neurodevelopmental impairment’ mediated by genetics.

He drew an analogy to myocardial infarction (MI) invol-

ving genes, environment, risk biomarkers (e.g. blood

pressure, blood sugar, lipids), pathology (atheroma), then

symptoms, and finally MI. He wondered whether risk

markers, ‘distal’ biomarkers (such as lipids in MI), prox-

imal biomarkers (such as abnormal ECG in MI), pre-

clinical syndrome, and clinical syndrome could also be

developed for psychiatric conditions. He posited a

‘multilevel psychiatric diagnosis of the future’.

Dr Cuthbert, as the final panel presenter, focused on the

‘NIMH Research Domain Criteria (RDoc) Project’ as a

needed ‘framework for research’ separate from the DSM

– ‘go back to ground zero … organize research in differ-

ent ways from the DSM approach’, reflecting that ‘any

nosology is imposing a structure on a much more complex

2 Psychiatric Genetics 2014, Vol 00 No 00


reality’. Greater focus on ‘dimensions of observable

behavior and neurobiological mechanisms’ with ‘a lot of

interest in pathways, polygenes, functional gene groups’

and a need to ‘also try to focus research on developmental

processes’ would be critical to advancing the under-

standing of psychiatric disorders. He highlighted the

work of Lips et al. (2012) on functional synaptic gene

groups as risk factors for schizophrenia as an example of

polygene pathways.

Affective disorders and PTSDGenetics of mood disorders (reported by Nagaraj S.

Moily)

Dr Emma Knowles (Yale University, USA) presented her

work on identifying genes involved in major depression

using whole-genome sequencing. This analysis was

completed on 530 Mexican-American individuals from

extended pedigrees and showed two novel variants on

chromosome 3 that were associated significantly with

depression. One was located at ∼ 188.0Mb (χ2= 40.15,

P= 2.35× 10− 10) and the other at ∼ 67.0Mb (χ2= 35.21,

P= 2.96× 10− 9).

Dr Alexander Charney (Icahn School of Medicine at

Mount Sinai, USA) presented bipolar disorder (BPD)

GWAS data of 13 741 cases and 19 762 controls. The

meta-analysis combined four independent GWAS data-

sets after accounting for overlap: a Swedish national

sample (2121 cases, 5894 controls), a UK sample (2595

cases, 5645 controls), a sample of mixed European

ancestry (1512 cases, 1338 controls), and the previously

published PGC BPD (Psychiatric GWAS Consortium

Bipolar Disorder Working Group, 2011) sample (7481

cases, 9250 controls). Eight regions were identified that

showed genome-wide significance. These included

genes associated with the calcium channel and the fragile

X mental retardation protein (FMRP). Copy number

variant (CNV) burden analysis carried out on a subset of

BPD samples did not reach significance and showed a

limited contribution of CNVs toward the risk for BPD.

Dr Pamela Sklar (Icahn School of Medicine at Mount

Sinai, USA) spoke on the progress of the Psychiatric

Genomics Consortium (PGC) for BPD. The wave 2

samples of PGC were updated with additional samples of

∼ 8643 cases and 13 949 controls from Germany, Sweden,

Norway, and the USA, bringing the total to 47 719 sam-

ples: 19 631 cases and 28 088 controls. The analyses of

the entire dataset yielded additional genome-wide sig-

nificant findings as well as strong support for previous

loci. Eight genome-wide significant loci were reported in

the primary analysis and an additional 10 loci were

reported in the replication analysis. She also presented

her preliminary work on shared loci and shared pathways

of BPD with schizophrenia. She emphasized the impor-

tance of continued efforts to increase the number of

samples to uncover more associations with BPD and to

consider genetic analyses across current diagnostic

boundaries.

Dr Fernando Goes (Johns Hopkins University School of

Medicine, USA) spoke about next-generation sequen-

cing of synaptic genes in familial major depressive dis-

order (MDD). He elaborated the role of synaptic

pathophysiology in the etiology of major depression and

that the synapse is the primary target of most anti-

depressant drugs. Next-generation sequencing of all

exons in 2011 genes that comprise the vast majority of

genes expressed in the synapse was performed in 350

cases from the Genetics of Recurrent Early-Onset

Depression family collection and equal numbers of con-

trols to identify rare variants involved in major depres-

sion. Gene-based and pathway-based mutational burden

analyses did yield some interesting hits, but they did not

survive Bonferroni correction nor were they exome wide.

Some of the suggestive findings involved intriguing

genes involved in actin regulation and a moderately sig-

nificant enrichment of rare damaging single-nucleotide

polymorphisms (SNPs) in synaptic genes.

Dr Catherine Schaefer (Kaiser Permanente Research

Program on Genes, Environment and Health, USA)

reported on the GWAS of MDD in the Kaiser

Permanente Research Cohort. She highlighted the

availability of comprehensive longitudinal electronic

medical records and phenotypic clarity linked to genome-

wide genotype data in the present study. More than 9000

cases of MDD and 54 000 controls were screened for

analysis. The GWAS analysis was carried out using Plink

v1.07 (http://pngu.mgh.harvard.edu/ ~ purcell/plink/download.shtml) using an additive logistic regression model

that controlled for age, sex, and ancestry principal com-

ponents. A single SNP, rs35350027, on the SHROOM3gene on chromosome 4, reached a genome-wide level of

statistical significance (odds ratio= 0.85; 95% confidence

interval: 0.81, 0.90; P= 5.14× 10− 9). Eight other SNPs

were associated with MDD with P-values less than 10− 5.

The study did not replicate or overlap the suggestive

associations of the findings in the MDD Working Group

of the Psychiatric GWAS Consortium other than a single

SNP on chromosome 7 that is near a suggestive signal in a

male-only analysis. The results reflect the heterogeneity

and complexity that remain obstacles for understanding

the underlying genetics of MDD.

Dr Gerome Breen (Institute of Psychiatry, King’s

College, London) cited the lack of significant findings in

GWAS studies of MDD (Major Depressive Disorder

Working Group of the Psychiatric GWAS Consortium

et al., 2013) and spoke on the PGC2 for MDD. The

present study samples involved almost doubling of the

sample size of the cases (n= 18 000) and a large increase

in the number of controls (n= 25 201), but did not yield

any genome-wide significant hits, and provided few

suggestive findings. The issue of increasing the power of

XXI World Congress of Psychiatric Genetics Akpudo et al. 3

http://pngu.mgh.harvard.edu/~purcell/plink/download.shtml

http://pngu.mgh.harvard.edu/~purcell/plink/download.shtml


the study by increasing the sample size was discussed for

MDD. The importance of phenotypic reliability and

adjustment for heterogeneity in MDD were also

highlighted.

The BPD sequencing consortium (reported by Anna

Alkelai)

Dr Jared Roach (Institute for Systems Biology) discussed

high-throughput sequencing of pedigrees, ‘family geno-

mics’, and presented a sequencing study that included

200 whole genomes from 43 BPD families and 158 from

34 non-BPD families. This study showed candidate var-

iants in different genes. One of them is located in

MTRNR2L1. Pathway analyses of the data implicated the

involvement of gene networks, that is, in the voltage-

gated calcium channels and GABA pathways.

Dr Guy Rouleau (McGill University) discussed the fail-

ure of linkage and GWAS to explain the high BPD her-

itability. He highlighted the importance of looking for

multiple highly penetrant rare variants to fully explain

the missing heritability in BPD. He presented a high-

throughput sequencing family-based study that focused

on a well-defined subphenotype of BPD (patients with a

positive response to lithium therapy). Some promising

BPD susceptibility variants (∼12 variants in each family)

were found by prioritization of rare (< 1%) variants that

fully or partially segregate with affected status within

families. Some of these variants are located in genes such

as OSBPL6, SH3BP5, and HTR3A. He also presented

analyses still in progress from lymphoblastoid cell lines

that explored the biological effect of the novel sequenced

variants.

Dr Francis McMahon (NIMH Intramural Research

Program, National Institutes of Health) introduced the

‘AMBiGen: A Next-Generation Sequencing Study in the

Plain People’ project. He presented a SNP chip and

whole-exome sequencing study in an Amish and

Mennonite homogeneous BPD sample. A total of 170

BPD individuals were studied, most of whom came from

one large Amish kindred. The SNP genotyping was

performed using the HumanOmniExpress BeadChip Kit

(Illumina Inc., San Diego, California, USA) and the

Genome-Wide Human SNP Array 6.0 (Affymetrix, Santa

Clara, California, USA). Identity by descent and shared

segment analyses were carried out using Beagle and

Plink software. These analyses found suggestive candi-

date chromosomal regions such as 1p34.3, harboring

many genes. Whole-exome sequencing was performed in

50 selected cases and candidate variants were found in

genes such as EPHA10, SCRN3, and HEATR2.

Dr Eli Stahl (Icahn School of Medicine at Mount Sinai)

presented a large-scale whole-exome sequencing study in

three different BPD cohorts (BLISS, Swedish BPD

case–control cohort, and BRIDGES). No overall sig-

nificant findings were found. However, one notable

variant was found in the GRIN2C gene. This session

emphasized the importance of data sharing and it was

made known that additional groups were needed to join

the consortium.

Genetics of PTSD (reported by Markus Reitt and Jana

Strohmaier)

Although traumatic events are frequent and experienced

by ∼ 50–85% of Americans, only about 8% develop post-

traumatic stress disorder (PTSD). The rate is higher in

individuals who experienced combat (18%) and twice as

high in women than in men. The experience of stress

activates the hypothalamic–pituitary–adrenocortical

(HPA) axis, which also influences memory consolidation

and retrieval. Chronic or extreme stress can cause long-

lasting alterations of the HPA axis. The contribution of

epigenetic mechanisms toward stress and trauma include

DNA methylation, chromatin remodeling, and

RNA/miRNA. An example of how epigenetics and

environment factors (particularly early life stress) may

interact is the finding that childhood trauma deregulates

the stress response through DNA demethylation in the

FKBP5 gene (Klengel et al., 2013).

Dr Kerry Ressler (Emory University) spoke about the

intergenerational transmission of learned olfactory fear in

rodents – a possible tractable animal model for the

intergenerational transmission of PTSD in humans (Dias

and Ressler, 2013). The olfactory system is associated

closely with emotion. The receptors in the nose directly

project through the olfactory bulb to the prefrontal cor-

tex, amygdala, and hippocampus. The olfactory system

has a high level of neural plasticity. Stem cells in the

olfactory epithelium are constantly replacing new olfac-

tory sensory neurons. Three days of olfactory fear con-

ditioning in mice have already been shown to enhance

the number of neurons in the nose and axons to the bulb

and may model epigenetic alteration in primary brain

regions critical for fear memory. These neuroanatomical

and epigenetic alterations may also be inherited. In fact,

two generations of naïve offspring of trained male mice

(fathers and offspring never came in contact) showed

enhanced behavioral sensitivity to the paternal-

conditioned odor and significantly enhanced numbers

of odor receptors, which seem to result from methylation

changes of the specific receptor gene that detects the

conditioned odor. In a cross-fostering design, neuroana-

tomical and behavioral changes in the offspring were

associated with their biological parent’s training. These

findings as well as methylation-specific imprinted DNA

of odor receptor genes after conditioning in sperm sug-

gest that transgenerational effects can be inherited

through changes in parental gametes.

Professor Akira Sawa (Johns Hopkins School of

Medicine) spoke about the disturbance of epigenetic

control on stress response and dopaminergic neuro-

transmission in mental illness. Psychiatric disorders often



develop in late adolescence and young adulthood, a time

of increased social stress that may disrupt normal brain

maturation and influence behavioral patterns in adult-

hood. This process may be mediated by epigenetic

mechanisms. In an animal model, social stress was oper-

ationalized through social isolation (Niwa et al., 2013).After 5–8 weeks of isolation, altered prepulse inhibition

was observed, possibly mediated by the HPA axis, but

only when combined with an appropriate genetic risk (in

this case, dominant-negative DISC1 in the GXE mice).

The application of a glucocorticoid receptor antagonist

normalized the prepulse inhibition alteration and

decreased extracellular dopamine levels. This influence

of glucocorticoids on dopamine levels may be because of

epigenetic alteration. In fact, increased DNAmethylation

of a specific projection of dopamine neurons (mesocor-

tical projection) was observed. The increased DNA

methylation continued for months and could be normal-

ized by the glucocorticoid receptor antagonist. The

results suggest that genetic interaction with adolescent

stress drives long-lasting cortical changes.

Dr Elisabeth Binder (Max-Planck Institute of Psychiatry)

spoke about the identification of genetic variants for

gene–environment interactions using early trauma-

moderated methylation and expression quantitative trait

locus (eQTL) analysis. In a study within the Grandy

Trauma Project, genome-wide gene expression and

DNA methylation data in peripheral blood and SNP

genotype data were investigated to identify expression

and methylation quantitative trait loci (eQTLs and

mQTLs) that were moderated by exposure to child

abuse. Participants (N= 394) were from a poor African-

American population with a high rate of traumatization.

Analyses were controlled for age, sex, BMI, substance

abuse, and adult trauma as well as multiple testing.

Almost 450 unique transcripts were identified. In the

language delay blocks of SNP regions that moderate

transcription, an enrichment of DNAse I hypersensitive

sites was observed as well as an enrichment of gluco-

corticoid receptor-binding sites. Twenty-seven percent

of the SNPs that altered transcription in interaction with

child abuse also alter methylation patterns. A significant

over-representation of eSNPs among SNPs showing a

gene–environment interaction on psychiatric symptoms

was observed in a larger (N> 3000), independent cohort.

Dr Douglas E. Williamson (University of Texas Health

Science Center at San Antonio) spoke about patterns of

DNA methylation and gene expression in PTSD in post-

mortem tissue, preclinical, and clinical samples. In five

PTSD cases and five controls, post-mortem tissue ana-

lyses, methylation patterns of the posterior cingulate

cortex, and the medial olfactory cortex were analyzed.

Changes in methylation were observed in the medial

olfactory cortex. The two top genes hypermethylated in

PTSD cases were GRIA2 and KDM6B. Then, the

Illumina Human Methylation 450k array was run in DNA

samples from the medial olfactory cortex of eight PTSD

cases and eight controls. Two novel genes ALOX5 and

ATXN71 were hypomethylated in PTSD cases.

The first GWAS of PTSD was published by Logue et al.(2013). In addition, Dr Guia Guffanti (Columbia

University) reported the results of a GWAS on 413

women from Detroit. A novel RNA gene lincRNAAC068718.1 was identified and replicated as a risk factor

for PTSD (Guffanti et al., 2013). As a next step, they

identified an associated pathway of a cluster of nine

genes associated with immune-related diseases. Dr Joel

Gelernter (Yale University, USA) presented a study using

the ‘SSADDA’ (Semi-Structured Assessment for Drug

Dependence and Alcoholism). They could identify

PTSD patients among a large drug and alcohol addiction

sample and performed a GWAS on 6000 individuals.

Using this and a replication sample of almost 3600

patients, TLL1 was found to be a risk locus (Xie et al.,2013). This association was significant for European-

Americans, but not African-Americans. Kerry Ressler

(Emory University, Georgia, USA), focusing on ‘inner

city trauma’, studied ∼ 8000 individuals. They found an

association with the gene FKBP5, which is a mediator of

the HPA response. The risk allele was also associated

with a decrease in hippocampus size. Murray Stein

(UCSD, Departments of Psychiatry and Family &

Preventive Medicine, San Diego, USA) presented the

‘Army Starrs’ project featuring 57 000 participants and

34 000 available blood samples and its subproject the

‘New soldier study’, for which a pre–post deployment

design has been developed. However, no results are

available as yet. The definition of PTSD is a major issue

as there is much heterogeneity and comorbidity involved,

and PTSD from military experiences may represent a

select subgroup not comparable with other PTSD phe-

notypes studied globally.

Schizophrenia (reported by Julia Steinberg)Dr George Kirov (Cardiff University, Wales) discussed

the penetrance of 70 CNVs implicated in schizophrenia,

developmental delay (DD), autism (ASD), or congenital

malformations (CMs) (Kirov et al., 2013). Almost all

confer a much higher risk for DD/ASD/CM than for

schizophrenia; for the remaining CNVs, the difference in

the risk for DD/ASD/CM versus schizophrenia was small

and not significant. Considering all schizophrenia and

DD/ASD/CM together, the mean penetrance of the 70

CNVs varied between 10 and 100% (mean 41%). The

selection coefficients of the CNVs were correlated

strongly with the overall penetrance estimates (r2= 0.6).

It was noted that the inclusion of prenatal death as a

phenotype could increase the penetrance estimates of

some CNVs.

Dr Karolina Aberg (Virginia Commonwealth University,

USA) presented a methylome-wide association study

(MWAS) from blood of 750 patients with schizophrenia



and 750 controls. A total of 141 differentially methylated

regions were identified at a false-discovery rate of 0.01.

Although 139 of these regions were located within or near

genes, few overlapped promoter regions; some of the

associations, including the top hit in FAM63B, were

replicated in an independent sample. A network analysis

linked a large number of the genes to immune response

and hypoxia pathways. Dr Aberg argued that mouse

studies support the use of blood tissue to study methy-

lation, given the limited availability of post-mortem brain

samples.

Dr Stephan Ripke (The Broad Institute, Harvard and

MIT, USA) reported the latest PGC schizophrenia

GWAS results. He showed that as the sample number

increased from just a few thousand to now 80 000 sam-

ples, significant numbers of risk loci also increased con-

siderably so that currently there are over 100 that are

significant for schizophrenia. He showed examples of

GWAS hits that would be useful as drug targets and have

also been implicated in the past, such as DRD2, gluta-mate receptors, and calcium channel genes. A gene set

analysis by Dr Tune Pers, one of his collaborators,

showed significant associations with 74 biological path-

ways, including gene sets related to dendritic and neuron

spines, postsynaptic density, and synaptic transmission.

Polygene scores from the PGC significantly predicted

schizophrenia in an independent dataset [r2= 0.14 com-

pared with 0.05; (Ripke et al., 2013)].

Dr Danielle Posthuma (VU University) presented the

association analysis of schizophrenia with gene sets

characteristic for three glial cell lineages: astrocytes, oli-

godendrocytes, and microglia. For each of the three glial

cell types, a set of genes associated with that cell type,

but neither neurons nor the other two cell types was

compiled from a literature search (Goudriaan et al., 2013).The gene sets for oligodendrocytes and astrocytes, but

not for microglia, were associated significantly with the

risk of schizophrenia; for astrocytes, this included subsets

related to signal transduction, gene transcription, and cell

processes, whereas the associated oligodendrocyte sub-

sets related to cell metabolism.

Dr Steven McCarroll (The Broad Institute) reported a

whole-genome sequencing study of 759 schizophrenia

cases and controls from the Genome Psychiatry Cohort.

The variant calls showed a concordance of greater than

99.8% with array-based genotypes. The schizophrenia

cases showed an excess of large CNVs; a new method

called Genome STRiP (Handsaker et al., 2011) was usedto identify additional deletions as small as 1 kb. In total,

over 20 000 CNVs of size 1 kb to 1Mb were detected, of

which 15% were multiallelic. Moreover, on examining

mobile elements, over 7800 novel ALU insertions were

discovered. The use of admixture to map the sequence

that did not align to the reference genome (Genovese

et al., 2013) showed that the missing regions largely fall

around the centromere. This approach showed that

CNVs at 1q21.1 considered to be identical varied at

megabase scales.

Dr Menachem Fromer (Mount Sinai, New York, USA)

presented an RNA-sequencing study of post-mortem

brains by the CommonMind Consortium. In the pre-

liminary analysis, prefrontal cortex samples of individuals

with schizophrenia (n= 228), BPD (n= 9), and healthy

controls (n= 240) were included. Cases and controls were

matched for age, and several other variables (including

sex, RNA quality, and brain bank) were accounted for.

The RNA-sequencing pipeline was optimized for tran-

script discovery. The genes expressed differentially

between schizophrenia cases and controls in a previous

study (Mistry et al., 2013) were found to mostly show

changes in expression in the same direction in the current

dataset; a detailed analysis for differential expression of

genes and transcripts is ongoing. The data will be made

available through Synapse (http://www.synapse.org)in 2014.

Autism and related neurodevelopmentaldisorders (reported by Branko Aleksic andIrene Pappa)Dr Christopher Walsh (Boston Children’s Hospital, USA)

spoke on ASDs and neurodevelopmental disorders in

which diagnosis is based on behavioral measures, typi-

cally at ages of 3–4 years. ASD are often associated with

comorbidities, such as cognitive impairment and epi-

lepsy. ASD are complex neuropsychiatric diseases, with

significant heritability, and a genetic architecture that

includes single genes, chromosomal abnormalities,

CNVs, and de-novo mutations (Sanders et al., 2012). Rarerecessive mutations are an important inherited mechan-

ism for ASD (Lim et al., 2013) and can be identified more

easily in consanguineous families. Consanguinity has

been associated previously with high rates of neurode-

velopmental disorders. Dr Walsh presented research

performed in 200 consanguineous families in the Middle

East and Pakistan. His research shows that diverse

genomic regions are responsible for ASD, intellectual

disability, and seizures and that there is significant

overlap with other neurodevelopmental, metabolic, and

synaptic disorders. He stressed the importance of mis-

sense alleles for the development of these disorders and

the need to discover more efficient ways to detect them

and access their functional impact. Whole-genome and

exome sequencing in American ASD patients has iden-

tified partial loss of function (LoF) in some gene-

regulatory regions. However, when compared with con-

sanguineous families, nonconsanguineous American

families show notable differences, including fewer de-

novo CNVs and a lower female : male ratio among pro-

bands. Nonconsanguineous families (e.g. from the USA,

in which parents are rarely related) have a rate of de-novo

CNVs as a cause of ASD of ∼ 5%, whereas normal


http://www.synapse.org


individuals have a rate of de-novo CNV of about 1%. In

contrast, affected children with ASD, when the parents

are first cousins, show a lower rate of causative de-novo

CNV than do affected children of unrelated parents. It is

likely that the overall rate of de novos is equal in all

families, but consanguineous families have a higher risk

of recessive mutations because of consanguinity; thus,

de-novo mutations represent a smaller fraction of the

overall disease-causing mutations.

Dr Julia Steinberg (Wellcome Trust Center for Human

Genetics, UK) presented data on the role of FMRP genes

in autism. Specifically, FMRP target sets contribute

toward ASD through different types of genetic variation

and genes disrupted by deleterious de-novo mutations.

Rare ASD-associated CNVs preferentially disrupt a sub-

population of FMRP targets with synaptic functions; this

same subpopulation of FMRP targets is also associated

with ASD diagnosis on the basis of SNP data. In addition,

individuals carrying multiple disruptions of FMRP tar-

gets, particularly those with synaptic functions, by rare

CNVs, are at a significantly higher risk for ASD.

Furthermore, she explained that mutations in genes

regulated by FMRP may contribute toward ASD through

two distinct genetic etiologies: (a) single disruptions of

embryonically upregulated FMRP targets that are

likely to be highly penetrant and ultra-rare or (b) less-

penetrant, multiple disruptions of nonembryonic,

synaptic FMRP targets, which act in combination to give

rise to ASD.

Dr Richard Anney (Trinity College Dublin, IE) carried

out large high-density meta-analyses combining data

from multiple studies including 6500 individuals with

ASD using the Illumina Human Exome bead chip. He

found a single, genome-wide significant, finding at the

ASTN2 locus on chromosome 9. ASTN2 in a rare CNV has

been implicated previously in ASD. He also carried out a

supporting replication study, indicating that common

variation also contributes toward ASD genetic liability.

Dr Christopher Poultney (Seaver Autism Center, Icahn

School of Medicine at Mount Sinai, USA) investigated

CNV deletions of between 1 and 30 kb in ASD using

whole-exome sequencing. The validation of 85% of these

deletions by quantitative PCR showed that the CNV

calling algorithm (XHMM) could accurately detect small

variation. Dr Poultney showed a significant (P= 0.017)

burden of these deletions in ASD cases, which may be

associated in as many as 7% of cases.

Dr Mark Daly (The Analytic and Translational Genetics

Unit, Massachusetts General Hospital, USA) examined

an etiologic role of low frequency [minor allele frequency

(MAF)< 1%] in ASD using exome array data from 12 510

individuals. He identified nine low-frequency/rare

single-nucleotide variants (SNVs) associated with ASD at

a P-value of less than 10− 3. Eight of the variants were

located within protein-coding genes: ANO1, COLEC12,

GJA9,MYCBP,MYH13, RRP8, SRRM5, STX5, TET2, andZNF428. Furthermore, Dr Daly showed significant

inflation of test statistics for low-frequency variants

(0.5%<MAF< 1%; λ= 1.038), which is highly unlikely

to occur by chance. The inflation was not observed for

rare variants (MAF≤ 0.5%; λ= 0.704), which suggests a

lack of power to detect the genetic effects. With

increased power from larger sample sizes, a targeted

exome genotyping strategy will provide a valuable

approach to elucidate the genetic basis of this complex

brain disorder.

Ian Blumenthal and the Talkowski Lab (Center for

Human Genetic Research, Massachusetts General

Hospital, USA) investigated the global transcriptional

consequences of reciprocal 16p11.2 CNVs using a cus-

tomized strand-specific RNA-sequencing protocol on

lymphoblasts from a unique cohort of 35 individuals from

seven multiplex ASD families, each harboring a segre-

gating 16p11.2 CNV, and showing heterogeneity of both

genotype and phenotype. The team also sequenced

RNA from the cortex of eight mice with the 16p11.2

syntenic region either deleted or duplicated and eight

sex-matched wild-type littermates. The most robust

expression alterations were observed within the 16p11.2

CNV region itself; however, interconnected networks of

dysregulated genes provided evidence for the con-

vergence of altered global gene expression on previously

identified ASD pathways and loci, as well as insights into

the importance of chromatin conformation on gene

expression.

Dr Harrison Brand (Center for Human Genetic Research,

Massachusetts General Hospital, USA) identified com-

plex chromosomal rearrangements (>3 breakpoints) in 15

individuals (26.8%), disrupting 45 genes, which is mark-

edly higher than the 2.8% predicted by cytogenetic

estimates. Of the 41 cases with canonical balanced

chromosomal aberrations, he found disruption of 27

genes among 26 individuals, a finding that emphasizes

the significance of cytologically visible chromosomal

abnormalities as a source of mutations with a significant

impact in human development and psychopathology.

Furthermore, Dr Brand implicated several novel genes

(e.g. CDK6, CTNND2) that may be associated with neu-

rodevelopmental disorders.

ADHD (reported by Christie Burton)

Dr Peter Holmans (Cardiff University, UK) shared find-

ings from a pathway analysis of GWAS hits and CNVs

from PGC attention-deficit/hyperactivity disorder

(ADHD) samples. For the analysis of CNVs (>500 kb),the top pathway enriched for CNVs in ADHD was

interleukin-6-mediated signaling (P= 9.59E− 08). These

CNVs were primarily duplications. Ion channel pathways

also showed enrichment for ADHD CNVs, specifically

nicotinic acetylcholine receptors, metabotropic glutamate

receptors, and GRM interactors, supporting Elia et al.



(2011). Other significant pathways included transforming

growth factor-β signaling and the synaptic pathway (in

particular the ARC complex). SNP data were analyzed

using ALIGATOR, but fewer pathways were enriched in

the GWAS than CNV data; only some pathways were

identified in both analyses (e.g. nicotinic acetylcholine

receptor).

Dr Andreas Reif (University Clinic of Würzburg,

Germany) described findings from the PGC cross-

disorder GWAS focusing on BPD and ADHD samples.

These disorders are comorbid, coheritable (Faraone et al.,2012), and may share some similar phenotypes (e.g.

impulsivity). No genome-wide significant hits were

identified in the previous GWAS of BPD and ADHD

from the PGC, although there was an increased burden of

BPD risk genes in ADHD samples. In an additional

analysis of 5800 BPD cases and 6000 ADHD cases, more

genes were concordant than discordant between the two

disorders. Of note, two genome-wide significant markers

were identified in a meta-analysis of ADHD and BPD

(with age of onset < 21) GWASs. To further investigate

the shared phenotype between BPD and ADHD, the

performances of BPD participants with and without

ADHD were compared on a combined stop-signal and

go/no-go task measuring impulsivity. No group differ-

ences were observed when controlling for age. Thus, this

form of impulsivity may not be a shared phenotype

between bipolar and ADHD.

Dr Barbara Franke (Radbound University Medical

Centre, the Netherlands) spoke on methods to identify

mechanisms of the ADHD genes identified using

GWAS. One example is the Drosophila melanogaster (fruitfly) model; hyperactive flies were significantly enriched

for ADHD genes. DAT1 knockdown flies were also more

active and treatment with methylphenidate, a drug used

to treat ADHD, rescued this phenotype. Dr Franke

outlined a pipeline of methods to assess the function of

identified GWAS genes that includes bioinformatics,

model systems, and brain imaging (e.g. IMPACT pro-

ject). For the bioinformatics phase, she cited work by

Poelmans et al. (2011), which used pathway analyses and

systematic literature reviews to characterize a gene

landscape for ADHD related to neurite outgrowth. For

the model systems phase, she reported that DAT1

knockdown flies showed altered number of neurites,

branches, and branch length compared with controls. For

the brain imaging phase, data from the IMPACT project

using human tract-based spatial statistics that assesses

brain connectivity through white matter tracts were dis-

cussed. In 200 ADHD cases and controls, the DRD5genotype was associated with brain connectivity in var-

ious brain regions including the corpus callosum and the

cerebellum. These methods will help characterize risk

genes at multiple levels of analysis and our future chal-

lenge is to connect these levels of analysis.

Dr Ben Neale (Massachusetts General Hospital, USA)

discussed the findings to date from the analysis of the

PGC ADHD samples as well as the 23 and Me project.

The current ADHD GWAS includes 5621 cases. No

markers reached genome-wide significance, although the

top hit was intergenic. The analysis of the exome chip for

the PGC ADHD sample included 7000 samples (3065

ADHD, 3058 controls, and 783 unknown individuals who

are parents without a diagnosis). For the case–control and

family-based analyses, call rates were adequate for both

common and rare variants. On the basis of the

quantile–quantile-plots, no common variants were sig-

nificant. For the rare variants, the quantile–quantile-plot

showed some general deflation overall that may be

because rare SNPs may not meet the assumptions of the

asymptotic distribution. More samples are required for

the analysis of rare variants in this sample. Findings from

the meta-analysis of the 5800 self-identified ADHD cases

and 70 393 self-identified controls from the 23 and Me

project were presented. No markers reached genome-

wide significance; however, using the polygenetic risk

score from the PGC some P-values were marginally sig-

nificant. Dr Neale suggested that these findings were

similar to those initially observed for schizophrenia,

suggesting the possibility for more hits with more sam-

ples. Finally, the PsychChip that will be used for future

PGC analyses was discussed. The array chip uses the

HumanCoreExome chip as a backbone and will contain

an additional 50 000 variants specifically related to psy-

chiatric disorders. The PGC is targeting to run 30 000

ADHD cases on the PsychChip.

Other childhood-onset disorders (reported byEnrico Cocchi)Dr Irene Pappa (Universitair Medisch Centrum

Rotterdam, the Netherlands) presented a GWAS meta-

analysis for aggression (N: preschool= 15 670,

school= 16 315) and showed no significant finding, but

some suggestion of increases in schizophrenia (preschool)

and autism (school) known risk loci. She concluded that

future studies of complex behaviors should include

known rare variants found in other disorders such as

schizophrenia and autism, and suggested that pheno-

typing needs improvement (parents vs. self-reported vs.

observed assessment) and the differentiation of situa-

tional aggression (Dodge and Coie, 1987) from other

types of aggressive disorders.

Dr Cynthia M. Bulik (University of North Carolina,

Chapel Hill, USA) described a GWAS of anorexia ner-

vosa (AN) from the Wellcome Trust Case Control

Consortium 3 (WTCCC3) and Genetic Consortium for

Anorexia Nervosa (GCAN). It is the largest GWAS for

any eating disorder ever performed. Results indicated

various genetic risk loci for eating disorders and showed

that no highly associated MDD signal could explain AN

case–control status.



Dr Philip Mitchell (University of New South Wales,

Sydney, Australia) carried out a brain imaging study with

genetic correlations in a youth cohort at high genetic risk

for BPD. This was a prospective longitudinal study

(N= 352, 158 at risk for BPD, 130 controls, and 64 BPD,

age: 12–30 years). Dr Mitchell's study showed that in

BPD, there are differences (fMRI) in emotional regula-

tion and functional connectivity. The correlation

between the polygenic risk score and fMRI functional

connectivity showed interesting results only when eth-

nicity weighted, highlighting the necessity of further

analysis.

Dr Kimm van Hulzen (Radboud University Nijmegen,

the Netherlands) reported on the sharing of genetic

background between ADHD and BPD. Although the

symptoms overlap [Cross-Disorder Group of the

Psychiatric Genomics Consortium; Genetic Risk

Outcome of Psychosis (GROUP) Consortium, 2013], this

does not seem to be genetically supported

[Cross-Disorder Group of the Psychiatric Genomics

Consortium; Genetic Risk Outcome of Psychosis

(GROUP) Consortium, 2013]. These investigators

selected young bipolar patients (onset< 21 years) to

further investigate this relationship. A meta-analysis of 14

GWAS studies of BPD patients and ADHD patients

younger than 21 years old found two GWAS significant

results in a cross-disorder analysis and 1515 suggestively

loci, suggesting individual genes to be further investi-

gated. However, a polygenic analysis with ADHD as the

training set and BPD as the target set showed no sig-

nificant overlaps.

Dr Andrew E. Jaffe (Lieber Institute for Brain

Development, Baltimore, Maryland, USA) reported on

DNA methylation in development and neuropsychiatric

disorders of the post-mortem human brain. The analysis

(N= 351, lifespan-second trimester fetal) showed that

DNA methylation markedly changes at birth (single CpG

changes= 78.5% fetal vs. nonfetal). A total of 118 genes

showed a different expression because of methylation.

These differentially methylated regions were enriched

with genomic loci of risk for schizophrenia and several

other common diseases.

Dr Matcheri Keshavan (Boston, Massachusetts, USA)

reported on a longitudinal study of 168 adolescents at

familial risk for schizophrenia, aged 10–22 years, who had

no psychotic disorders at entry compared with schizo-

phrenic patients. He concluded that at-risk patients show

prodromal symptoms and clinical features that predicted

psychosis. Genome and environmental data strengthened

the predictive power.

Dr Shane McCarthy (Cold Spring Harbor Laboratory,

New York, USA) reported an analysis of de-novo variants

that supported a genetic overlap of schizophrenia with

autism and suggested that nonsense variants and chro-

matin remodeling play a role in the pathogenesis of

psychiatric disorders. He also reported that there was a

higher than expected load of de-novo mutations in

sporadic trios (P= 0.01), with some new potential candi-

dates identified. He concluded that family designs are a

very useful way to narrow heterogeneity and exome

sequencing helps to prioritize the importance of patho-

genetic mutations, combining it with GWAS approaches.

Substance abuseRole of methylation and chromatin modification

(reported by Lea K. Davis)

Dr Jian Feng (Mount Sinai School of Medicine, New

York, USA) began the session with a study of the epi-

genetic regulation of cocaine action in mouse nucleus

accumbens. His group performed next-generation

sequencing, RNA sequencing, and chromatin immuno-

precipitation sequencing (ChIP-seq) on DNA and RNA

extracted from mouse nucleus accumbens after 7 days of

cocaine administration. They mapped histone modifica-

tion (i.e. H3K4m1/3, H3K9m2/3, H3K36m3, and

H3K27me3) and gene expression changes induced by

cocaine and found ∼ 250 genes (1% of the total tran-

scripts) and 4106 isoforms (5% of total transcripts) that

were differentially expressed. They then mapped regions

of coinciding chromatin and gene expression alterations,

termed ‘chromatin signatures’. They identified 29 such

signatures and highlighted A2BP1 (aka rbfox1) as a spli-

cing factor that was enriched at the location of chromatin

signatures, suggesting that A2BP1 may be a primary

molecule involved in cocaine-mediated changes in gene

expression.

Dr Anne West (Duke University Medical Center, North

Carolina, USA) presented findings on the roles for the

methyl-DNA binding protein (MeCP2) in addiction.

Previous work has shown that altered expression of

MeCP2 can alter stimulant-induced addictive behaviors.

Dr West and colleagues hypothesize that the phosphor-

ylation of MeCP2 Ser41 can be induced by amphetamine

and may modulate addiction. To test this hypothesis,

they developed a mouse knock-in that selectively

removed the Ser41 phosphorylation site. The mice

developed normally, but showed increased rates of self-

administration of amphetamines, increased locomotor

activity after two doses of investigator-administered

amphetamines, and reduced excitability of medium

spiny neurons compared with wild-type mice. They thus

proposed that the phosphorylation of MeCP2 Ser41functions to limit the circuit plasticity in the nucleus

accumbens that underlies addictive behaviors.

Dr Chris Pierce (University of Pennsylvania) presented

evidence from a rat model showing that cocaine exposure

resulted in epigenetic and behavioral changes detectable

in the male offspring of sires that self-administered

cocaine. He showed that BDNF mRNA levels, protein

levels, and promoter acetylation were increased in the

medial prefrontal cortex and that there was a



corresponding decrease in the self-administration of

cocaine in the male offspring of cocaine-exposed sires.

The administration of a BDNF receptor antagonist

restored the self-administration of cocaine to wild-type

levels in male offspring of cocaine-exposed sires.

Dr Gustavo Turecki (McGill University, Montreal,

Canada) presented an analysis of DNA methylation pat-

terns of dopamine pathway genes in post-mortem brain

tissue from individuals with a history of cocaine depen-

dence and drug-naïve individuals. They used reduced

representation bisulfite sequencing to detect DNA

methylation at single-nucleotide resolution in the dorsal

and ventral striatum. In the caudate, they detected 71

CpGs differentially methylated in cases compared with

controls (61 hypomethylated and 10 hypermethylated).

In the nucleus accumbens, they detected 20 CpGs dif-

ferentially methylated between cases and controls (19

hypomethylated and one hypermethylated). Sixteen of

these sites were common to the caudate. Differentially

methylated sites clustered on chromosomes 20 and 21.

Substance use disorders (reported by Te-Tien Ting,

Christie Burton, and Enrico Cocchi)

Dr Brien Riley (Virginia Commonwealth University,

USA) reported on findings from a GWAS in a homo-

geneous Irish sample of alcohol dependence (AD) cases

and controls. SNPs in the collagen 6A3 (COL6A3) gene onchromosome 2 were genome-wide significant. Functional

studies in multiple model organisms show consistent

effects on ethanol response of changes in COL6A3 and

three other genes (the Krueppel-like factor 12, KFL12gene on chromosome 13, the Ryanodine receptor 3,

RYR3, gene on chromosome 15, and the Protein-

O-mannosyltransferase 2, POMT2, on chromosome 8) also

significant in the GWAS.

Dr Shaunna Clark (Virginia Commonwealth University,

USA) presented findings from a MWAS. A combined

analysis of the MWAS and GWAS was used to clarify the

mechanism of alcohol exposure or inherited suscept-

ibility toward alcohol use. Only CNTN4 showed a sig-

nificantly consistent association with alcohol use on the

basis of the combined MWAS and GWAS results and

another replication study. Further examination showed

significant evidence that methylation of CNTN4 medi-

ated the relationship between rs1382875 and alcohol use.

This inherited susceptibility can lead to reorganization of

neural circuits and is considered to contribute toward

addiction.

Ms Emily Olfson (Washington University, St Louis,

USA) described findings from the Collaborative Study on

the Genetics of Alcoholism (COGA) on the interplay

between genes and risk factors in the development of

early drinking behaviors. Cox proportional hazards

regression was used to model drinking milestones start-

ing at age of first drink. Preliminary results supported an

interaction between an ADH1B variant and smoking in

the development of first alcohol use among adolescents

and young adults. The presence of the ADH1B protective

allele was associated with a decreased risk for first

symptom onset. This protective effect appeared to be

reduced among individuals who had previously initiated

smoking.

Dr Georgy Bakalkin (Uppsala University, Sweden)

reported findings on the epigenetic mechanism of pro-

dynorphin (PDYN) on emotion regulation and reward in

human post-mortem brain of individuals with alcoholism.

DNA methylation of the PDYN promoter was examined

in prefrontal cortices. CpG methylation in CpG islands

(CGI) was found to be correlated with PDYN expression

levels. In addition, an upstream regulatory factor-2

(USF2) was colocalized with PDYN protein in neurons

and bound to the PDYN CGI in studies using ChIP-

qPRC. PDYN mRNA/peptides, CpG methylation in the

CGI, and USF2 correlated with each other. CGI deme-

thylation in alcoholics may promote USF2-mediated

recruitment of histone modifiers to the promoter,

resulting in PDYN activation. The challenge is that these

measures change across the lifetime and cannot be seen

in a post-mortem design.

Dr Margit Burmeister (University of Michigan, USA)

presented gene–environment interactions from the

Michigan Longitudinal Study, a sample of 463 families.

Two major haplotypes are formed by GABRA2 SNPs, one

of which was previously significantly associated with

alcoholism. The results showed that this haplotype was

associated with female impulsivity and linked with insula

activation during monetary reward anticipation.

Impulsivity was a mediator for the GABRA2 effect on

alcoholism. Patients with the risk haplotype of GABRA2were more likely to engage in problem behaviors during

adolescence when not monitored by parents. This shows

that individuals carrying this haplotype are more sus-

ceptible to environmental influence.

Dr Shirley Hill (University of Pittsburgh, Pennsylvania,

USA) spoke on brain structural changes as important

endophenotypes of AD familial risk. The findings on the

basis of three-generational family data showed a greater

risk for developing substance disorders and at an earlier

age among the offspring of AD families than those of

control families. To uncover morphological endopheno-

types associated with familial risk for AD, three important

variables (i.e. sex, developmental changes, and exposure

to alcohol and drugs) were assessed. On the assumption

that the occipit-frontal cortex (OFC) modulates the

amygdala in regulating emotion, OFC/amygdala ratios

were constructed and related to age of onset to develop

substance use disorders. Using survival analysis, it was

found that those with smaller OFC to amygdala ratios had

an earlier onset of substance use disorders. This was

found within the entire sample as well as within the high-



risk sample. These results suggest that even among off-

spring from multiplex families, brain morphology can

assist in predicting the likelihood of developing sub-

stance use disorders in adolescence and young adulthood.

Dr Yasmin Hurd (Icahn School of Medicine at Mount

Sinai, New York, USA) spoke on her vast body of trans-

lational work on the genetic and neurobiological

mechanisms underlying drug addiction that combines

human genetics with animal models. For example, she

showed the link between opioid-related genes and brain

changes associated with opioid use in both humans and

animals. Compared with controls, the post-mortem brains

of a homogenous sample of European heroin users

showed reduced μ-opioid receptor (MOR) expression as

well as altered expression of several components of the

mitogen-activated protein kinase intracellular signaling

pathway induced by MOR activation, including extra-

cellular signal-regulated kinase (ERK) 1. Downstream

targets of the mitogen-activated protein kinase pathway

such as the transcription factor ets-like kinase (ELK) 1

were also dysregulated in heroin users, particularly in the

striatum, a region well known for its role in the effects of

drugs of abuse. Notably, ELK1 expression in this brain

region was associated with a risk allele in the OPRM1

gene that codes for MORs. Further, ELK1 expression

was related to a history of heroin use in the human

sample. In an animal model of heroin use, heroin intake

through intravenous self-administration was also corre-

lated with ELK1 protein levels in the striatum. These

findings suggest a possible mechanism underlying the

neurobiological changes associated with substance abuse

disorders (Sillivan et al., 2013). One of her main findings

is that the genetics of the opioid neuropeptide system

relates to inhibitory control, negative affect, and reward

choice. She also investigated the association between

epigenetic modulation and the regulation of neuronal

systems that relates to inhibitory control, affect, and

reward. In addition, she developed an in-vivo imaging

and molecular strategy to examine the neural network

directly linked to cell-specific molecular disturbances.

For example, remote inhibition of neurons in the peria-

mygdala nucleus expressing the PDYN gene (dis-

turbances of which were detected in heroin abusers and

suicide victims) was found to lead to selective activation

of the extended amygdala network linked to stress and

anxiety. Finally, a striking finding of the effects of drug

exposure detected in animals was the impact on affective

and anxiety-like behavior across generations.

Dr Joel Gelernter (Yale University School of Medicine,

New Haven, USA) performed a GWAS of AD traits in

three populations, two USA (N= 16 087), and a Chinese

sample (N= 313). The USA populations replicated risk

loci in alcohol dehydrogenase 1B (ADH1B) and alcohol

dehydrogenase 1C (ADH1C) genes and identified novel

risk loci mapping to the ADH gene cluster on chromo-

some 4. Combining the USA populations resulted in a

strong association on chromosome 2 (P< 10− 17). It was

related to an intergenic region (rs1437396) between

coiled-coil domain containing 88A (CCDC88A) and

mitochondrial translational initiation factor-2 (MTIF2).CCDC88A was differently expressed in alcoholics and its

product interacts with both disrupted in schizophrenia 1

(DISC1) and vascular endothelial growth factor A

(VEGFA), associated with AD (Heberlein et al., 2010).The Chinese sample showed a risk locus on alcohol

dehydrogenase 2 (ALDH2) associated with AD

(P= 4.73× 10− 8) and two AD-related phenotypes:

flushing response and maximum drinks in a 24-h period.

These results are of central importance because a GWAS

analysis identified different variants but on the same

gene for the USA populations and in the same pathway

(hepatic metabolism) among all the populations under

analysis.

Dr Arpana Agrawall (Washington University, St Louis,

USA) carried out a meta-analysis of genome-wide studies

of AD. Twelve GWAS were analyzed. There was an

absence of replication across studies. However, the most

promising genes found were fukutin (FKTN)-fibronectintype III and FSD1L domain containing 1-like (FSD1L)and ectonucleotide pyrophosphatase-phosphodiesterase

3 (ENPP3). Consistent with Dr Gelernter’s results, the

most interesting locus was found on chromosome 4, in

the ADH cluster.

Dr John Nurnberger Jr (Indiana University, USA) studied

variation in the phenotype for single genes related to AD

on the basis of developmental stage, sex, and ethnicity

using the COGA sample (1164 families of AD and 233

families of controls). ADH1B variations were associated

with AD in both groups (adolescent and young adults).

New data show three SNPs in ADH4 with potential

protective effects in homozygotes. The other relevant

gene identified was γ-aminobutyric acid A receptor-α2(GABRA2), where conduct disorder symptoms were

associated with AD only in carriers of the high-risk

rs279871 genotype, particularly in those with age of

onset of conduct problems in early adolescence. Recent

data from Perry et al. (2013) suggest that daily life events

can predict the risk for AD, but only in males with the

GABRA2 risk genotype. Predictive phenotypes for the

ADH genes include drinking frequency and alcohol

problems; predictive phenotypes for GABRA2 include

conduct disorders.

Dr Dayne Mayfield (University of Texas, Austin, Texas,

USA) studied the integrated miRNA, mRNA, and pro-

tein coexpression networks in brains of ethanol-treated

mice. The importance of miRNA is that they have huge

network regulatory potential, ‘fine-tuning’ capabilities

and they appear to be associated with psychiatric dis-

orders (Kolshus et al., 2013) and addiction (Nunez et al.,2013). Fifty-two differently expressed miRNA families

were found in mouse AD models and 32 in humans;



among these, 14 families’ results overlapped (P< 10− 5).

The Toll-like receptor 4 (TLR4) MyD88-dependent

pathway seems to be the best associated and the most

functionally plausible.

Genetics of smoking behaviors (reported by Emily

Olfson)

Dr Eric Johnson (RTI International, USA) described the

first study reporting an association between nicotine

dependence and variants in a region on chromosome 15,

which includes the CHRNA5–CHRNA3–CHRNB4 choli-

nergic nicotine receptor subunit genes (Saccone et al.,2007). The nonsynonymous variant rs16969968 in

CHRNA5 emerged as a consistent variant in GWAS and

was shown to play a functional role (Bierut et al., 2008).To better understand whether there are additional dis-

tinct loci in this region on chromosome 15, haplotype

analysis was carried out. Findings from this analysis

indicate that the region harbors multiple loci associated

with smoking behaviors, particularly in individuals of

African descent.

Dr Alison Goate (Washington University School of

Medicine, St Louis, USA) presented data from functional

studies that implicate additional variants in the same

above region on chromosome 15 for risk of nicotine

dependence. Wang et al. (2009) found that common

noncoding variation upstream of CHRNA5 is associated

with mRNA expression in brain tissue as well as risk for

nicotine dependence and lung cancer. Recently, this

region associated with mRNA expression has been nar-

rowed by examining individuals of African descent. In

the adjacent nicotinic receptor subunit gene, CHRNB4,Haller et al. (2012) found that rare missense variants at

conserved residues were associated with a lower risk of

nicotine dependence. In-vitro studies of these CHRNB4rare variants indicate that they increase cellular response

to nicotine. Taken together, these studies of both com-

mon and rare variation provide additional mechanisms

beyond the well-established rs16969968 variant by which

this region on chromosome 15 contributes toward

smoking-related problems.

Dr Jerry Stitzel (Institute for Behavioral Genetics,

University of Colorado, USA) presented a mouse model

of the well-established rs16969968 human variant that

causes an Asp398Asn change in the CHRNA5 (nicotinic

receptor α5 subunit gene). Mice with the Asn risk allele

consumed more nicotine than wild-type mice and

showed greater positive reinforcement from nicotine

intake. With cocaine, the reverse effect was observed: the

Asn risk variant was associated with a protective effect for

self-administration of cocaine. Reversal of risk for two

substances, nicotine and cocaine, has been reported

previously in humans by Grucza et al. (2008). Beyondbehavioral changes, this variant alters brain chemistry in

mice. In the ventral tegmental area and the nucleus

accumbens, the variant was associated with

neurotransmitter changes in response to nicotine intake,

but did not considerably alter baseline neurotransmitter

levels. In the habenula, where CHRNA5 is considered to

be important, the baseline levels of several neuro-

transmitters were altered, possibly reflecting a difference

in predisposition. Overall, these findings show that one

SNP identified in humans can have marked effects on

both behavioral responses to substances and brain

chemistry in a controlled model system.

Dr Nancy Saccone (Washington University School of

Medicine, St Louis, USA) focused on the importance of

translating knowledge of the genetics of nicotine

dependence into smoking cessation. Chen et al. (2012)identified a significant interaction between pharmaco-

logic cessation treatment and genetic variation in

CHRNA5. Specifically, those at highest genetic risk for

nicotine dependence were least likely to quit smoking,

and these individuals benefited most from the addition of

pharmacological treatment to counseling. This latter

point is emphasized by examining the number needed to

treat (NNT), defined as the average number of patients

who must be treated for one to benefit. In the high-risk

genetic group, adding pharmacotherapy to counseling

resulted in an NNT of four compared with an NNT of

over 1000 in the low-risk genetic group. More recently,

Chen et al. (2013) examined how variation in the nicotine

metabolizing gene CYP2A6 contributes toward cessation

of treatment response. Among those with high-risk geno-

types for both CHRNA5 and CYP2A6, the NNT is further

reduced to 2.6. These findings show how specific geno-

types can guide cessation treatment decisions.

Cross-disorder analyses (reported by IsabeleG. Giori)Dr John Hettema (Virginia Commonwealth University,

USA) discussed GWAS targeting in shared anxiety dis-

order susceptibility. His ongoing work has been a meta-

analysis with pre-existing samples. He then carried out a

replication analysis with different samples. He obtained

no significant findings with the case–control studies.

However, when using a quantitative phenotype, he had

GWAS significant hits on chromosome 10, chromosome

2, and chromosome 4.

Dr Elaine Green (Plymouth University, UK) discussed

CNVs in a novel large BPD sample in comparison with

schizophrenia. Large rare CNVs have been implicated in

the etiology of schizophrenia; however, their role in BPD

has been less well studied and remains unclear, with

some studies reporting an increased incidence of CNVs

and others not. The incidence of rare (< 1% in general

population) CNVs (>100 kb in size) in BPD (n= 2591)

(BDRN sample, http://www.BDRN.org) was compared

with that in a large dataset of patients affected with

schizophrenia from the UK. Significantly fewer deletions

of greater than 1Mb were observed in BPD (P= 0.0012).

They also noted fewer duplications in BPD cases of


http://www.BDRN.org


500 kb to 1Mb in size (P= 0.012). These findings were

driven to some extent by deletions at known schizo-

phrenia loci, in particular deletions greater than 1Mb at

the following loci: NRXN1, 3q29, 15q13.3, 17p12, 17q12,

and 22q11.2. The findings were consistent with the

group’s previous findings (Grozeva et al., 2010) indicatingthat schizophrenia and BPD differ with respect to CNV

burden in general, and in particular in the possession of

large, rare deletions.

Dr Douglas Ruderfer (Icahn School of Medicine at

Mount Sinai, USA) presented findings from a preliminary

analysis of exome sequencing in BPD, schizophrenia, and

controls from a matched Swedish population. He dis-

cussed the careful attention required in comparing indi-

viduals from different sequencing runs and implemented

a three-way matching scheme across all phenotypes on

the basis of genetic information and sequencing metrics.

After matching, he reported a significant enrichment of

very rare disruptive mutations in calcium channel genes

in BPD cases, similar to enrichment observed in schizo-

phrenia in the same dataset.

Dr Verneri Anttila (MGH/Broad Institute, USA) dis-

cussed the Brainstorm Project. He reviewed the genetic

architecture of psychiatric disorders and highlighted the

successes of recent GWAS consortia in both neurological

and psychiatric diseases, as well as positing an approach

to leverage of those results as a way to understand the

comorbidity of diseases of the brain. The study builds on

the previous work within the PGC in probing the genetic

cross-phenotype links and expands on that work to

include neurological diseases as well. The project was a

collaboration between several different consortia, and

represents an effort to understand the common genetic

causes of neurological and psychiatric diseases. Initial

results are from across-disease single marker and pathway

analyses, which suggest an excess sharing of GWAS sig-

nals and increased pathway aggregation in the neurolo-

gical and psychiatric diseases studied.

Dr Giulio Genovese (Stanley Center/Broad Institute,

USA) presented results from a new large cohort of USA

individuals of African descent. He showed an increase in

large deletions and duplications in both schizophrenia

and bipolar patients compared with controls. The schi-

zophrenia results in European samples were replicated in

these samples with African ancestry.

Dr Mark Reimers (Virginia Commonwealth University,

USA) highlighted that SNPs in regions that are functional

are more likely to have consequences for psychiatric or

other phenotypes than SNPs in regions that have no

apparent function. He described a novel empirical Bayes

method for integrating genomic functional information

with genetic association, which increased the power to

detect risk SNPs. For the shared genetic risk of schizo-

phrenia and BPD, this method found an enrichment for

genes related to neuron differentiation, development of

dendrites, and postsynaptic density. The differential risk

between the disorders was enriched in genes for nicotinic

cholinergic signaling.

Dr Chunyu Liu (University of Illinois, Chicago, USA)

spoke on using brain molecular QTLs to identify novel

risk genes shared by multiple psychiatric diseases. He

used brain eQTL data to reanalyze GWAS signals of 11

diseases and traits. All psychiatric disease GWAS signals

showed significant enrichment of brain eQTL SNPs.

Moreover, some diseases shared brain eQTL SNPs in

their GWAS signals more than by chance, indicating

their shared genetics/genes. A novel region on chromo-

some 3 was identified as harboring shared risk genes for

bipolar, schizophrenia, and obsessive–compulsive dis-

order (OCD).

Genetic testing and clinical carePersonal and clinical genomics and returning results to

the consumer (reported by Adeniran Okewole and Jana

Strohmaier)

Dr Robert Green (Brigham and Women’s Hospital, USA)

introduced the different types (e.g. array testing,

sequencing, karyotyping), purposes (e.g. clinical testing,

testing within a research environment, biobanking), and

contexts (e.g. medical, consumer or research driven,

prenatal, preconceptive, counseling available or infor-

mation through internet, incidental findings) of genetic

testing. The expectations of medical benefit to genetic

testing are high. The company, 23 and Me, already has

more than 400 000 customers and particularly individuals

are very interested in finding genetic explanations for

their diseases. The costs for whole-genome sequencing

have decreased considerably. For these reasons, impor-

tant issues need to be addressed, such as the potential

harm and uncertainty of a result, the tremendous amount

of data, and handling of incidental findings. Data from

the REVEAL (the Risk Evaluation and Education for

Alzheimer’s Disease) study were presented, suggesting

that disclosure of APOE test results do not have a huge

psychological impact on individuals (Ashida et al., 2010).Testing results do not cause significant degrees of anxi-

ety and the testing profile is not correlated with the

degree of anxiety. Anticipatory anxiety previous to result

disclosure predicts stress levels after results have been

disclosed. However, after testing, individuals seek

healthcare examinations that are related to the results and

not necessarily useful. Those with a positive test for

APOE4 were more likely to modify lifestyle to reduce

cardiovascular risk (Chao et al., 2008), follow better

dietary controls (Vernarelli et al., 2010), and take out long-

term care insurance (Zick et al., 2005). In the NIH pro-

gram exploring the use of genomic sequencing in new-

born healthcare (http://www.nih.gov/news/health/sep2013/nhgri-04.htm), parents are surprisingly interested in the

testing results even if they know what information they

will receive.


http://www.nih.gov/news/health/sep2013/nhgri-04.htm

http://www.nih.gov/news/health/sep2013/nhgri-04.htm


Dr Greene also discussed a study of the motivations and

impact of customers using personal genomics services.

He reported findings from the Impact of Personal

Genomics (PGen) study, addressing the question of

whether access to genomic information shifts the client’s

risk paradigm. Interest in genetic testing was found to be

related to concerns about specific disease risk, risks for

children, and drug response for those with health con-

cerns. Patients with known diagnoses such as BPD and

multiple sclerosis were particularly interested in their

testing, implying that individuals were simply trying to

understand themselves. A sizable proportion were plan-

ning to talk to their family and friends about their results.

Although 28.4% had discussed their results with a pri-

mary care provider, 11% had had tests, examinations, and

procedures attributable to the new genetic information.

Predictors of anxiety after testing included poorer self-

reported health and increased baseline anxiety.

Dr Scott Roberts (University of Michigan, USA) pre-

sented genetic risk disclosure in Alzheimer’s disease,

focusing on the ε4 allele of APOE, carriers of which were

at an increased risk but that was neither necessary nor

sufficient for Alzheimer’s disease. APOE disclosure was

thus used as an illustrative paradigm of the risks and

benefits of disclosure. He also discussed findings from

the REVEAL study, in which it was found that women,

Whites, middle aged individuals (vs. older adults), with

higher socioeconomic status, and healthy ‘monitors’ (vs.

blunters) all had a higher test uptake. Personal utility

(increased awareness of disease/health risks, advance

planning, the idea that ‘knowledge is power’), rather than

clinical utility, informed the seeking of testing. Risk

discordance was reported in 47%. A condensed protocol

was found to be just as effective in communicating

information as was a more elaborate protocol and tele-

phone was just as effective as communicating in person.

With respect to impact of information, no adverse psy-

chological outcomes were experienced by participants.

Behavioral changes prompted by the information inclu-

ded that ε4 carriers made long-term insurance changes

and a significant change to dietary supplementations

(P< 0.001).

Dr Atul Butte (Stanford University, USA) spoke about

the decrease in costs for sequencing and described a

future in which healthcare insurance may someday offer

discounts for individuals who provide their genetic

information. When he started his work, there was no

‘master database’ that included all identified disease-

associated SNPs and risk alleles, and using only internal

funding his team constructed such a database, now

numbering nearly 20 000 papers, identified from the lit-

erature nearly half a million SNPs for 7400 diseases. He

further talked about the odds ratio, a measure of asso-

ciation that may not be applicable in medical settings.

The likelihood ratio might be better as it is able to be

combined across multiple tests and may be less

susceptible to spurious or incidental findings (Morgan

et al., 2010). He stressed that physicians must be trained

to understand, incorporate, and communicate genetic

results (Ashley et al., 2010) and spoke about the value of

risk prediction and knowing one’s own risk for medical

and pharmacological prevention (Dewey et al., 2011).

Individuals can be educated about their risks and how

they can change environmental and behavioral factors to

decrease their risk. Visualization tools may help physi-

cians and the tested individual better understand the

results.

Dr Uta Francke (Stanford University; Senior Medical

Director at 23 and Me, USA) spoke about the right of

everyone to access and understand his/her genetic

information. 23 and Me offers quick and easy access to

one’s own genetic make-up. One can sign up online and a

saliva sample is delivered by mail. Genotyping is per-

formed using the Illumina OmniExpress Plus

Genotyping BeadChip and thousands of custom

designed variants for ∼ 1 000 000 SNPs are examined.

Results include information on the carrier status for 50

Mendelian diseases, 121 health risks on the basis of

GWAS and association study results (e.g. ANK3 for BPD,

APOE for Alzheimer’s), and 24 drug responses. All this

information can be important for family planning, plan-

ning for old age. The standard for 23 and Me is that risk

loci must have been established in at least 1000 cases and

controls and replicated in an independent study before

they are reported to the customer. The customer receives

links to up-to-date research literature [Cross-Disorder

Group of the Psychiatric Genomics Consortium; Genetic

Risk Outcome of Psychosis (GROUP) Consortium,

2013]. 23 and Me collects raw data and this database is

growing rapidly. Over 80% of customers consent to the

collection of phenotypes, which allows for new dis-

coveries. 23 and Me also investigates how customers

respond emotionally and behaviorally to the disclosure of

results. Thirty-two carriers and 31 noncarriers who had

decided to know their BRCA1 and BRCA2 carrier status

were interviewed (Francke et al., 2013). None reported

extreme anxiety and four carriers reported moderate, but

transient anxiety. Female carriers sought medical advice

and risk-reducing procedures. Some men felt a burden

because of the fact that their carrier status implies genetic

risk for female relatives. Except for one individual, all

appreciated knowing their carrier status.

Dr A. Cecile J.W. Janssens (Emory University, Georgia,

USA) spoke about the high predictive power of DNA

testing for monogenic diseases (e.g. Huntington disease)

and the lower power for multifactorial diseases (e.g. dia-

betes, cardiovascular disease). For risk prediction, it is

important to ask what is being predicted in which

population. Genetic information is more reliable for

matching individuals or diagnosing (e.g. paternity testing,

rare congenital syndromes) than for prediction

(e.g. pharmacogenetics, common/complex diseases,



nutrigenomics). In complex diseases, most traits are only

partly heritable. She discussed the relationship between

heritability and predictive ability of a test. A test cannot

be very predictive if the heritability of the predicted

disease is low (e.g. < 25%). Also, the complexity of a

disease, that is, the variety of factors causing the disease,

and with common alleles of small effect, all influence its

predictability. However, risk testing despite nonperfect

models has benefits on a population level in reducing

morbidity and mortality (Janssens and van Duijn, 2010).

Dr Paul Appelbaum (Columbia University, New York,

USA) spoke on the issue of incidental findings. Research

on incidental findings is a priority focus of the Ethical,

Legal and Social Implications (ELSI) Research Program

of NHGRI (http://www.genome.gov/10001618). The

American College of Medical Genetics has now released

recommendations for 24 conditions that should system-

atically be disclosed to the patient (Green et al., 2013). Inall, 234 researchers of the US genetic research commu-

nity completed an online questionnaire and 28 an

extensive semistructured interview to understand their

views of and experiences with incidental genetic research

findings (Appelbaum et al., 2013). Ninety-five percent of

respondents would disclose information about highly

penetrant, actionable findings; over 60% would disclose

information on high-penetrance alleles even if no inter-

vention is available; 80% would disclose information on

modest-penetrance alleles with available interventions;

and 16% would prefer to disclose a list of variants from

the entire genome. Although respondents endorsed a

long list of information to be discussed with participants

before obtaining informed consent for return of inci-

dental findings, they would like to spend 30 min or less

on the process. Dr Appelbaum suggested that alternative

models of informed consent were needed in place of

traditional consent, in which the decision about receiving

results is made before onset of study participation. In a

staged consent, the decision about receiving results is

made close to the disclosure of results, thereby allowing

consideration of current life circumstances. A mandatory

list of results defines what must be disclosed and sim-

plifies the consent process. The consent for and dis-

closure of results can also be outsourced.

Dr Sarah Hartz (Washington University in St Louis

School of Medicine, St Louis, USA) started with the

observation that although information about genetic risk

factors had improved, no system existed for reporting

genetic results to study participants. There is never-

theless an ethical duty to report results. Her study

reported ‘incidental genetic results’ (lung cancer, breast/

prostate cancer, colorectal cancer, heart attack, and dia-

betes type 2) to 50 heavy smoking individuals. Over 90%

of the participants found the results worthwhile and

discussed their results with a relative, doctor, or friend.

Over 80% reported increased motivation to quit smoking

and to change their diet or exercise. With respect to

psychological symptoms, 31% of the study participants

had moderate to severe anxiety at baseline, whereas 71%

had depression at baseline. No significant change from

baseline was found after counseling.

Isaac Kohane (Boston Children’s Hospital, USA)

advanced the argument that ASD requires an ‘expansive

integrative perspective’. This was in response to the

question of what to do with unexpected ‘incidental’

genetic findings (Kohane et al., 2006). He observed that

although ASD genetic research had produced consider-

able information on immune and synaptic mechanisms,

there was a lack of overlap between communities,

amounting to ‘academic blindness’. Analysis of data

suggested that different comorbidities lead to different

clusters of presentation. He therefore suggested that

bioinformatics would help to overcome disciplinary

blinders. Large population studies, improved sequen-

cing, as well as systematic and comprehensive pheno-

typing would also be beneficial.

What can we recommend to clinicians and the public?

(reported by Ajeet B. Singh)

One session was aimed at ultimately writing a statement

that would represent the ISPG containing recommen-

dations about how to use commercial DNA testing in

psychiatry. Themes for the session included the accel-

erating uptake of already commercialized genetic tests in

psychiatry, marked progress in the field since the last

ISPG guidelines were posted in 2009, the pressing need

for updated guidelines to assist both the public and

clinicians, and finally the consideration of potential harms

arising from misapplication of test information.

Dr Francis McMahon (President of ISPG) began by

reflecting on the need to update the 2009 ISPG guide-

lines and articulated potential uses of testing as ‘differ-

ential diagnosis, prediction of treatment outcomes,

identification of high risk individuals … preventative

strategies’. However, there is a need to ensure that

genetic biomarkers could be assayed reliably, are robustly

evidence based, and have an effect size sufficient to

enable clinical utility above current clinical practices. He

reflected that ‘genetic testing is already here in psy-

chiatry’, with companies actively marketing them. Thus,

‘should the psychiatric genetics community weigh in?’

He presented pros and cons, the ‘yes’ case being more

resonate, articulated on a slide as ‘Yes – genetic testing is

being marketed and used, we have the expertise, clin-

icians want/need help, patients are confused/mis-

informed, psychiatric disorders pose unique issues for

genetic tests’.

Dr Margit Burmeister (University of Michigan, USA)

discussed how pharmacogenetics of warfarin has evolved

to a clinically translatable stage over several years.

‘Variants of VKORC1 (vitamin K epoxide reductase

complex subunit 1 gene) are estimated to explain 25% of


http://www.genome.gov/10001618


the variability of dose’. This clinically relevant genetic

variant translates to an optimal dosage varying 20–30-fold

between patients. She added that pharmacokinetics has

shown some relevant effect sizes and ‘compared to

GWAS nearly Mendelian effects’. Her impression was

that pharmacodynamics had provided less clinically use-

ful findings and that the path ahead was principally for

pharmacokinetic pharmacogenetics. She reflected that

CYP450 2D6 metabolizer variation status in some indi-

viduals leads to an overdose or ineffective treatment, and

such information a priori could avert such unwanted

outcomes. Dr Burmeister cited data suggesting atypical

antipsychotic weight gain appears to be associated with

polymorphisms of rs489693 (Malhotra et al., 2012). Shespeculated that pharmacogenetic information may help

prescribers choose between typical and atypical anti-

psychotics on the basis of such information, as well as

pharmacogenetic prediction of tardive dyskinesia risk

(Zai et al., 2013). Finally, she highlighted that rare but

dangerous side effects such as Stevens–Johnson syn-

drome from aromatic anticonvulsants such as carba-

mazepine could be predicted by the HLA-B*1502genotype. She concluded that ‘clinicians need to be

educated that time is ripe for genetic testing for some

variants now’.

Dr Elliot Gershon (University of Chicago, USA) high-

lighted that despite being rare, ‘the most potent genetic

risks known in psychiatry are related to CNVs’. He cited

the example of the deletion in 22q11.21 being associated

with a 68.25% risk of schizophrenia (Malhotra and Sebat,

2012). He cautioned against adopting tests with an effect

sizes too small for clinical utility, but added that ‘aggre-

gate risk of a polygenetic component may become usable

in counselling’. He concluded with the need to reflect on

the possible ethical ramifications of such testing, in par-

ticular, the risk of stigma and issues of pregnancy plan-

ning and termination on the basis of parental and

antenatal genetic risk profiling (Gershon and

Alliey-Rodriguez, 2013).

Dr Lynn DeLisi (VA Boston Healthcare System, USA)

recalled attending the WCPG in 1998 in Bonn, Germany.

During that meeting, an excursion was made to a psy-

chiatric facility where thousands of schizophrenic

patients were ‘euthanized’ in the mistaken belief that

this could help end a cycle of heritable schizophrenia.

Dr DeLisi emphasized that there is still a ‘gap in

knowledge between we know as researchers and what

the public thinks and wants’. She pointed out that the

growth in commercial testing was occurring with a ‘lack of

regulations’ and ‘lack of informed consent or under-

standing of what is being gotten’ by consumers. ‘Some

companies offer expert medical advice, but they lack the

legal capacity to do so’. Direct to consumer testing gives a

sense of empowerment and being in control of healthcare

decisions by consumers. She further emphasized that

genetic testing is not at the level of providing diagnosis,

but only risk of illness, and consumers needed to be

aware of this critically important fact when they bring

information to providers and expect interpretation. Most

providers do not believe that genetic information is

useful and do not have a good understanding of genetics.

Functional genomics (reported by Min-ChihCheng)Dr Joseph Dougherty (Washington University School of

Medicine, USA) applied the translating ribosome affinity

purification methodology to identify the comprehensive

in-vivo suite of ribosome bound mRNA in serotonergic

neurons in adult mice. He found genetic variants in

CELF6 that may contribute toward the risk of autism and

that the Celf6 mutant mice show partial autism-related

phenotypes (Dougherty et al., 2013). Thus, he suggested

that CELF6 is likely to be one gene that can influence

risk for some autism.

Dr Melanie Leussis (Emmanuel College, USA) showed

that decreased ankyrin G levels (a putative BPD gene)

were associated with altered dendritic synaptic spine

density and synaptic functions, and the alterations in

synaptic proteins were largely normalized by chronic

treatment with the lithium (Leussis et al., 2013).

Dr Melvin McInnis (University of Michigan, USA) gen-

erated induced pluripotent stem cell (iPSC) from four

BPD patients and three controls using retroviral trans-

duction with pluripotency factors, followed by differ-

entiated into neurons. He observed that expressions of

genes for membrane receptors, ion channels, and neu-

ronal transcription factors were different in cells derived

from BPD versus controls. Furthermore, exposure of

BPD neurons to lithium significantly altered their cal-

cium and glutamine metabolism compared with control

neurons.

Dr Panos Roussos (Icahn School of Medicine at Mount

Sinai School, USA) carried out a multiscale integration of

high dimensional datasets, combined with gene coex-

pression network analysis, to identify putative causal

SNPs and genes related to neuronal function and

synaptic neurotransmission in schizophrenia. Overall,

their results support the existence of convergent genetic

abnormalities in schizophrenia. Dr Sevilla Detera-

Wadleigh (HGB, NIMH) showed that mefloquine, a

drug known to induce neuropsychiatric symptoms,

induced phenotypes in iPSC-derived neural stem cells

(NSCs). Pretreatment with lithium or valproate sig-

nificantly protects NSCs from the adverse effect of

mefloquine on viability, suggesting that cell viability is

possible and high-throughput assays can be performed in

the search for compounds that mimic the effect of mood

stabilizers and other agents.

Dr Alexander Urban (Center for Genomics and

Personalized Medicine, Stanford University, USA) gen-

erated 25 iPSC lines derived from fibroblast biopsies



from seven patients with a 22q11 deletion and seven

controls and characterized these iPSC lines using geno-

mic and gene expression methods. Dr Urban summarized

that the iPSCs showed stable genomes and good neuro-

nal differentiation potential.

Dr Olli Pietiläinen (Institute for Molecular Medicine,

Finland) reported on a 240 kb ‘Finnish specific’ deletion

on chr22q11.22 including the TOP3-β gene was asso-

ciated with schizophrenia, and predisposed to schizo-

phrenia and intellectual deficit (Stoll et al., 2013). Their

results highlight the usefulness of population isolates in

studying rare variation underlying complex disorders.

GWAS (reported by Alison Merikangas andIrene Pappa)The PGC

Dr Patrick Sullivan (University of North Carolina, USA)

introduced the session by describing the highly suc-

cessful collaborative network, the PGC, which includes

work groups spanning all major classes of psychiatric

disorders including attention-deficit hyperactivity, autism

spectrum (ASD), bipolar, major depression (MDD),

schizophrenia, cross-disorders, a liaison with the

ENIGMA (Enhancing Neuro Imaging Genetics through

Meta-Analysis) project, and new work groups on AN,

OCDs, and PTSDs starting in the next year. This is the

largest experiment in biological psychiatry (i.e. > 400

investigators, 80 institutions, 30 countries> 170 000 cur-

rent cases, and 80 000 additional in the next year). The

newly designed PsychChip, an Illumina chip tagging

250 000 common SNPs, 250 000 exome variants, and

50 000 custom SNPs, will be used for GWAS, CNV, and

exome variation studies for $45 per chip plus processing

fees. Dr Sullivan highlighted the success of the schizo-

phrenia workgroup as an example of the progress that can

be made, and his appreciation to the contributing

investigators was noted.

Dr Michael O’Donovan (Cardiff University, UK) pre-

sented a summary of the results and future plans for

research on common variation in the PGC, citing findings

of 128 genome-wide significant hits for schizophrenia, 10

for BPD, and findings from the cross-disorder analyses.

In light of the polygenic nature of these conditions, he

described the large number of cases that will be neces-

sary, particularly for disorders such as MDD, which has a

lower relative risk than those of schizophrenia and BPD.

He described the next step involving eQTL dissection of

loci, indicating that these studies could inform

pathophysiology.

Dr Shaun Purcell (Mount Sinai School of Medicine, New

York, USA) spoke about the value of pursuing studies of

rare variation in psychiatric disorders, particularly of

highly penetrant single gene loci that can inform the

mechanism of action of disease genes and delineate more

homogeneous subgroups for analysis. He presented

examples of a trio-based Bulgarian sample and a Swedish

case–control sample that showed excess burden of very

rare gene-disruptive mutations across ∼ 2500 genes,

without enrichment of de-novo LoF variants. Despite the

technical challenges in harmonizing datasets, he noted

the importance of consortia and me(t/g)a-analyses in rare

variant discovery and potential models of collaboration.

Dr Benjamin Neale (Massachusetts General Hospital and

the Broad Institute, USA) spoke about the genomics of

ASDs and the major goal of discovery of actionable bio-

logical pathways with rare variants providing particular

promise of success. LoF mutations as well as de-novo or

two-hit recessive markers may be particularly valuable in

ASDs. Challenges in this work include the reduced

power because of neutral rare variation, the very large

sample sizes required (e.g. 88 000 cases would be

required to obtain 80% power for a relative risk of 1.1),

and the complex genetic architecture of ASDs.

Naomi Wray, PhD (The University of Queensland),

described the genetic architecture of psychiatric disorders

that are characterized by genes with small effects. She

also described the importance of considering the archi-

tecture of specific disorders that appear to be highly

variable using the lower amount of variance explained by

genes for MDD than for some other psychiatric disorders.

She highlighted the need for collecting more information

on phenotypes, environmental risk factors, and genetic

information on the same sample to investigate their

combined contribution toward psychiatric disorders.

Dr Mark Daly (Massachusetts General Hospital and the

Broad Institute, USA) closed the session by stating that

genetics, big data, and statistics are delivering, with data

sharing as a key factor in the success. The major topics of

the discussion included the following: (a) the reliability

and accuracy of sequencing technology; (b) the need for

more active recruitment of additional samples, particu-

larly those with environmental risk information and

additional phenotypic information; and (c) the develop-

ment of a database for rare variants including patho-

genicity information with input from clinical geneticists,

which would be particularly valuable for the future.

In his ‘Young Investigator Award’ talk, Dr Stephan Ripke

(Massachusetts General Hospital; Broad Institute, USA)

highlighted research in genetics as a driving force to our

understanding of biology. His presentation was mainly

focused on the efforts of the PGC, the challenges, and

the successes it yielded over the last few years. First, he

gave the example of Crohn’s disease, where early GWAS

research showed more than 70 genome-wide significant

sites. Dr Ripke stressed the importance of genetics in

drug development (Plenge et al., 2013) through the

example of statins, where previous GWAS research in

hyperlipidemia indicated genetic sites with small effects

but huge clinical significance. Contrary to somatic dis-

eases, the psychiatric field faces more challenges. He



gave a small historical tour of PGC, beginning in 2009

with relatively small samples of schizophrenic patients

and ever growing. Vast efforts led to more than 100 dis-

tinct genetic regions being associated with schizophrenia

(Ripke et al., 2013). Among the new genes was the

dopamine receptor 2, DRD2, long implicated in schizo-

phrenia. Moreover, calcium channels, glutamate recep-

tors (GRM3), sex-linked genes, and the immune system

have emerged as components of schizophrenia’s genetic

architecture.

The use of novel statistical methods tounderstand genetic architecture (reported byDavid T.W. Chen)Dr Lea K. Davis (University of Chicago, USA) presented

on the additive genetic risk (chip heritability) using

Tourette syndrome (TS) and OCD as examples.

Interestingly, the results showed that chip heritability

were quite similar to twin estimates (h2 for TS= 0.58;

OCD= 0.37). Polygenicity was observed, with some

chromosomes contributing larger portions (chromosome

15 for OCD). Also, common and rare variations appeared

to contribute equal portions to the heritability of TS

(MAF< 0.05, h2= 0.13), but rare variations made no

contribution for OCD. Finally, h2 estimates by brain

eQTL were 33 and 59% (TS, OCD, respectively). A

shared genetic correlation was also found (r2= 0.41;

P= 0.002).

Dr Gerhard Moser (University of Queensland, Australia)

described a single model for GWAS (Erbe et al., 2012)that maps causal variants, estimates the genetic variance

explained by all SNPs, and predicts phenotypes from

SNP genotypes. The Swedish schizophrenia cohort

(∼7000 case–controls) and the WTCCC (seven pheno-

types) were used. The accuracy of risk prediction

depends on the heritability and genetic architecture of

the trait. Less than 10 000 SNPs explained all of the

genetic variance for schizophrenia, with 98% each

explaining 0.0001% of the genetic variance. Compared

with other methods, this approach had higher prediction

accuracy for traits with relatively strong associations.

Dr Alexander Gusev (Harvard School of Public Health,

USA) showed findings from coding variations in schizo-

phrenia in the Swedish cohort (∼6400 case–control).

Recent GWAS chip heritability for schizophrenia has not

yet matched twin estimates. Using GCTA, common

coding heritability was estimated at ∼ 0.4. On breaking

down into noncoding regions [i.e. UTR, promoters,

DNase 1 hypersensitivity site (DHS), intergenic], the

DHS was found to be nominally significant for enrich-

ment. Observing consistency between exome chip and

GWAS data, this approach was applied to nine traits in

the WTCCC data. Similar enrichments for coding and

DHS regions were observed, especially with imputed

SNPs (20-fold for coding; six-fold for DHS).

Dr Kaitlin Samocha (Massachusetts General Hospital;

Broad Institute, USA) presented on the contribution of

de-novo variation to ASD. Despite high heritability

(70–90%), only 10–20% have known lesions (chromoso-

mal abnormality or FMR1 gene silencing). Recent

reports of sequencing ∼ 950 families showed approxi-

mately two-fold excess of de-novo ‘loss of function’

(LoF) variants, implicating neither pathways nor disease

processes. To develop a clearer expectation, she devel-

oped a probability model of genome-wide de-novo rates

using the 1000 Genomes data. With this method, a sig-

nificant enrichment for LoF de-novo mutations in the

low IQ ASD group only was observed. Furthermore,

approximately two-fold enrichment for de-novo LoF

mutations (P= 1.44E− 6) for FMRP gene targets for all

ASD samples was observed. Subdivided by IQ,

approximately three-fold enrichment (P= 1.48E− 7;

odds ratio=∼ 6) was observed only in the low IQ ASD

group notable for an over-representation of individuals

with atypical cognition and female sex. No excess was

observed in cases with IQ of at least 100.

Dr Eli Stahl (Icahn School of Medicine, Mt Sinai, New

York, USA) discussed the genetic architecture of schi-

zophrenia in the Swedish study (∼12 000 participants)

using the polygenic risk score profiling approach. Results

for schizophrenia showed a plateauing effect with

increasing number of SNPs, suggesting a difference in

genetic architecture from other diseases such as rheu-

matoid arthritis. To better understand these differences,

a simulation (ABPA) of polygenic risk score profiling was

utilized. The results showed that 50% of the variance was

explained with ∼ 8000 SNPs. Compared with GCTA, a

larger portion of the variance was explained.

Dr Michael E. Talkowski (Massachusetts General

Hospital, Harvard Medical School, Broad Institute, USA)

discussed the role of structural variation in neuro-

psychiatric diseases. He sequenced all classes of

structural variation, including small or ‘cryptic’ balanced

chromosomal rearrangements (disrupting a single gene

without net gains or losses from the genome) using large

insert jumping libraries (3–4 kb fragments with 40–140×coverage) in 34 individuals with comorbid developmental

and psychiatric disorders. Structural variant calls were

refined by machine learning, followed by validation by

PCR/Sanger, which showed several potentially patho-

genic cryptic rearrangements directly disrupting genes

such as (CTNNA3, FAM155A, UBE2F) as well as the first

example of cryptic chromothripsis.

Biomarkers and endophenotypes (reported byTania Carrillo Roa)Sophie E. Legge (Cardiff University, UK) presented

results from two GWAS of schizophrenic patients with

clozapine-induced neutropenia (n= 64, < 1500 cells/

mm3) and severe clozapine-induced neutropenia (n= 18,

< 1000 cells/mm3) versus treated controls (n= 5469). The



sample was obtained from two UK sources: the

CLOZUK and the Cardiff COGS sample. Samples were

genotyped on two different Illumina arrays and further

imputed. Quality control and logistic regression were

performed separately on each array and meta-analyzed

using Plink (Purcell et al., 2007). She reported two

genome-wide significant SNPs (rs116019360 and

rs112478317 on chromosome 1p36.32 and 12q14.3,

respectively) associated with clozapine-induced neu-

tropenia and one genome-wide significant SNP

(rs75062547) associated with severe clozapine-induced

neutropenia. rs75062547 is located in an intron of

SLX41P; mutations in this gene have been associated

previously with Fanconi anemia (Kim et al., 2011).

Dr Lina S.C. Martinsson (Karolinska Institutet, Sweden)

investigated whether response to long-term lithium

treatment for BPD is associated with telomere length

(TL) (Martinsson et al., 2013). The study included 256

outpatients with BPD and 139 controls. TL was deter-

mined by quantitative real-time PCR in peripheral blood

leukocytes. Cases had 35% longer telomeres compared

with controls (P< 0.0005, partial η2= 0.13); TL was

positively correlated with lithium treatment duration

(P= 0.031, r2= 0.13, < 30 months) and negatively asso-

ciated with increasing number of depressive episodes

(P< 0.007). Lithium-responders had longer telomeres

than nonresponders, suggesting that increased telomer-

ase activity might be involved in response to lithium

treatment in BPD patients.

Dr Marco P.M. Boks (Rudolf Magnus Institute

Neuroscience, the Netherlands) discussed results from

an epigenome-wide association study (Illumina 450k) in a

cohort of Dutch military individuals deployed to

Afghanistan (n= 96). They hypothesized that DNA

methylation changes because of trauma lead to an

increase in PTSD. Blood samples and standardized

measures PTSD were collected before and 6 months

after deployment. This cohort was divided into sub-

groups on the basis of the level of combat trauma expo-

sure and the presence of PTSD symptoms. Results

showed two genome-wide associated CpG loci, with later

development of PTSD. These loci are located in the

PPP1R18 gene and the AMZ1 gene, which is proposed as

a candidate biomarker for the development of PTSD.

Dr Alexander B. Niculescu III (Indiana University

School of Medicine, USA) sought to identify differen-

tially expressed genes in blood in patients (n= 75) diag-

nosed with BPD during no suicidal ideation states and

high suicidal ideation states, as well as between patients

(Le-Niculescu et al., 2013). They used convergent

functional genomics to identify and prioritize from the

list of differentially expressed genes, biomarkers of

relevance to suicidality. They also examined whether

expression levels of these were altered in blood from age-

matched suicide completers. Thirteen of the 41 top

convergent functional genomics scoring biomarkers

(32%) showed a step-wise significant change from no

suicidal ideation to high suicidal ideation states and to the

suicide completer. Their top identified biomarker could

differentiate future hospitalizations because of suicidality

in a cohort of bipolar patients.

Dr Rakesh Karmacharya (Harvard Medical School, USA)

reported on the opportunity to generate neuronal cells

that contain genetic backgrounds from patients by

reprogramming iPSCs and neuronal progenitor cells

(NPCs) from fibroblasts. He reprogrammed iPSCs and

NPCs from patients with schizophrenia and BPD as well

as matched controls. Methodologies were developed to

differentiate these along neuronal lineages and mature

neuronal cultures, as well as assays to study image-based

phenotypes, and gene expression to identify unique

signals involved in these disorders. He hypothesized that

the vulnerability for disease will be reflected at the cel-

lular level when studying specific neuronal subtypes.

Dr Stephen J. Glatt (SUNY Upstate Medical University,

USA) spoke about a machine-learning algorithm that

distinguished children with ASDs from those developing

normally on the basis of gene expression levels in per-

ipheral blood samples. Their goal was to identify differ-

entially expressed genes between subsamples from

normal development, ASD, DD, or language delay chil-

dren as well as to replicate previous results in an inde-

pendent sample of ∼ 200 individuals. Expression levels

of differentially expressed genes were used to optimize

support vector machines classifying patients into clini-

cally derived diagnostic categories. The support vector

machine that obtained ∼ 70–90% accuracy in distin-

guishing ASD patients from normally developing chil-

dren in their initial results achieved an accuracy of 58% in

the replication sample. Further cross-validation, reopti-

mization of classifier parameters, and more precise

quantification of mRNA isoforms will aim to identify

more accurate and stable classifiers of ASDs and other

developmental disorders. Their results suggest that the

continued pursuit of a blood-based biomarker of early

autism is warranted.

Neuroimaging: the ENIGMA consortium (reported by

Kimm J.E. van Hulzen)

The ENIGMA consortium was presented as an inter-

national resource that brings together researchers in

imaging genomics. It aims to explore the genetic archi-

tecture associated with human brain structure and func-

tion to find the genetic underpinnings of psychiatric and

neuro-degenerative disease using structural and function

MRI and diffusion tensor imaging (DTI) and genome-

wide association data. The ENIGMA consortium started

in 2009 with three groups and now consists of 35 sites

contributing to the analysis. Free and standardized ima-

ging protocols, quality control guidelines, and genetic

imputation and association testing protocols are made



available for the participating sites, but also for indivi-

duals outside the consortium through the website, to

perform genome-wide association analysis. Meta-analysis

of results obtained from participating sites is carried out

by the support group of the ENIGMA consortium. This

session provided an overview of the consortium’s work

on structural MRI and DTI.

ENIGMA1 is a pilot project in which the support group

of ENIGMA carried out meta-analyses on hippocampal

volume, intracranial volume, and total brain volume

including over 16 000 individuals from 28 sites that span

five continents. Dr Derek Hibar (University of

California), member of the support group of the

ENIGMA consortium, showed that several genome-wide

significant variants were found to be associated with

hippocampal and intracranial volume. ENIGMA1 was

followed by ENIGMA2, an ongoing project that extends

the scope of ENIGMA1 by including subcortical volumes

(nucleus accumbens, amygdala, caudate, pallidum,

putamen, thalamus, as well as hippocampal and intra-

cranial volume). ENIGMA2 was initiated in 2012 and

involves additional participating sites. ENIGMA2 is

currently nearing completion and first results were pre-

sented in this session.

The collaboration of sites in the ENIGMA consortium

has led to the creation of working groups addressing a

range of important topics, including genetic influences on

white matter microarchitecture and integrity. This

integrity is measured through DTI fractional anisotropy

and is shown to be highly heritable. Variations in frac-

tional anisotropy are also strongly linked to disorders such

as schizophrenia and Alzheimer’s disease. The DTI

Working Group was formed with the initial goal of

developing a validated protocol to obtain reliable and

consistently heritable measures from images. Dr Emma

Sprooten (Yale University) showed that this protocol is

now easily implementable at many ENIGMA sites that

have DTI and genome-wide association data. In addition

to the DTI Working Group, the focus on neuroimaging

as an endophenotype for psychiatric and neurodegen-

erative disease has led to the formation of working groups

carrying out phenotypic meta-analyses examining the

association between brain measures and psychiatric

disease and neurodegenerative disease. The Bipolar

Disorder Working Group was represented by Dr Ole A.

Andreassen (Oslo University Hospital). Their approach is

to first determine patient versus control effect sizes for

subcortical volume differences, and second, explore

common genetic variants associated with the brain

structure abnormalities. Asymmetry in left and right

cortical structures will be taken into account in a later

stage. The Schizophrenia Working Group was repre-

sented by Dr Jessica Turner. She presented preliminary

results from a coordinated, large-scale meta-analysis

applying the same quality assurance metrics and statis-

tical models across independent datasets, with the goal of

identifying the strongest effect sizes across the various

subcortical abnormalities in schizophrenia. Given the

focus on neuroimaging as an endophenotype for psy-

chiatric and neurodegenerative disease, a cross-

consortium collaboration was established with the PGC

(ENIGMA2-PGC2). The ENIGMA2-PGC2 collabora-

tion aims to (a) find genetic variants that have both effect

on brain and effect on disease, (b) lend biological rele-

vance to findings of the ENIGMA consortium and the

PGC, and (c) validate endophenotypes.

Networks and pathways (reported by AdeniranOkewole and Julia Steinberg)Dr Amitabh Sharma (Northeastern University, Boston,

USA) discussed the application of protein interaction

networks to disease genetics. For the majority of dis-

eases, the associated genes were more tightly connected

to a network than expected by chance, suggesting that

the disease might result from localized perturbations in a

network. The tighter the connection of the genes asso-

ciated with the disease, the more similar the annotations

of the genes were based on gene ontology. Moreover, the

overlap or distance between modules for different dis-

eases reflected the similarity of the diseases on the basis

of overlap of symptoms, comorbidity, or similarity of the

gene annotations for the disease genes. Starting with a set

of associated disease genes, the network allows the

detection of a network module extended to other can-

didate genes, the ranking of all other genes on the basis

of the distance to the module, the identification of bio-

logical pathways overlapped by the module, and the

identification of drugs that modify the expression of the

module genes. During the discussion, tissue specificity of

gene expression and protein interactions emerged as an

important factor for future networks.

Dr Kristen Brennand (Mount Sinai, New York, USA)

presented results from modeling schizophrenia predis-

position using human-iPSCs (Brennand et al., 2011).

iPSCs derived from schizophrenic patients and controls

were differentiated into neural tissue corresponding to

the first trimester stage. A rabies transneuronal tracing

assay showed reduced connectivity and outgrowth of

neurons derived from iPSCs of schizophrenic patients.

However, this did not affect basal electrophysiology or

spontaneous Ca2+ transients. Gene expression differ-

ences between iPS-derived neurons from schizophrenia

patients and controls pointed to gene ontology processes

such as synaptic proteins, cell adhesion, and migration.

Some expression changes in known schizophrenia can-

didate genes could be reversed when the cells were

treated with loxapine. When NPCs were derived from

iPSCs of schizophrenia patients and controls, gene

expression and protein analyses showed some differences

related to synaptic transmission. The NPCs derived from

patients also showed higher oxidative stress and aberrant

migration.



Dr Olaf Sporns (Indiana University, USA) presented a

network analysis of the ‘human brain connectome’, a

structural map of human brain regions from MRI data

(Hagmann et al., 2008). The analysis showed features

such as the existence of brain region modules linked by

hub regions, unique regional connectivity fingerprints,

short path lengths between brain regions, and a promi-

nent structural core. Moreover, structural connectivity of

regions was found to predict functional connectivity. The

highly connected/central hub nodes were often con-

nected to each other (‘rich-club’ organization). The ‘rich-

club’ enables short, efficient information transfer and the

integration of information from diverse sources (Van den

Heuvel and Sporns, 2011). As 89% of the shortest paths

between brain regions were found to pass through a

member of the ‘rich-club’, damage in the ‘rich-club’ was

hypothesized to strongly affect the integrity and efficiency

of the network. A similar ‘rich-club’ was also detected in

the macaque brain (Harriger et al., 2012). The human ‘rich-

club’ members were found to be connector hubs, linking

resting-state networks determined from functional con-

nectivity. In schizophrenic patients, the density of ‘rich-

club’ connections was reduced; this correlated with a lower

global efficiency (Van den Heuvel et al., 2013), whereaslocal connection density was unaffected.

Dr Dennis Vitkup (Columbia, New York, USA) pre-

sented an analysis of gene networks underlying autism

and schizophrenia. He cited earlier reported clustering of

genes harboring inherited mutations (Feldman et al.,2008) and information on the similarity of genes on the

basis of coevolution, coexpression, and colocalization,

integrating these into a gene network (Gilman et al.,2011). He presented a study adopting a naïve Bayesian

integration approach to create a model, which was

investigated using NETBAG (Network Based Analysis

of Genetic Associations). CNVs, SNVs, and SNPs were

combined under one principled framework. Implicated

gene networks in ASD involved chromosome

modification/regulation, neuron signaling/cytoskeleton,

postsynaptic density, and channel activity (primarily cal-

cium channels). Schizophrenia clustered into a signaling/

cytoskeleton functional network and a chromosomal

modification/regulation network. Network connections

were found between genes implicated in ASD, intellec-

tual disability, and schizophrenia. He concluded by

forecasting 300–1000 causal genes in 20–40 pathways

involved in 5–10 biological processes. The genes in the

subnetwork showed high expression in the human brain,

with higher brain expression of the genes mutated in

females with autism compared with the genes mutated in

males. An analysis of genome regions associated with

schizophrenia showed a significant subnetwork with

functions in cell signaling similar to autism. This work

highlighted the need to adopt a computational approach

to integrate the diversity of genetic data into a framework

that would aid understanding of pathways and networks.

Dr Dick McCombie (Cold Spring Harbor Laboratory,

New York, USA) discussed the potential overlap of genes

involved in autism and schizophrenia, with a possible link

to chromatin remodeling. He presented data on exome

sequencing of 42 trios of unaffected parents and schizo-

phrenia offspring. Findings included a higher than

expected number of de-novo nonsense mutations that

overlap with ASD and intellectual disability, and

enrichment of genes involved in chromatin remodeling

and epigenetic mechanisms (CHD8, MLL2, MEPCP2,HUWE1).

Dr Daniel Howrigan (Massachusetts General Hospital,

Boston, USA) discussed emerging evidence for the

FMRP gene network enrichment among de-novo LoF

alleles in ASD and schizophrenia. He presented findings

from a Taiwanese trio schizophrenia sample. There were

1135 trios of sporadic cases, with 117 putative de-novo

LoF mutations. Four overlapping genes were found, all

four being in the FMRP network that is enriched in both

autism and schizophrenia. Second, he introduced the

PsychChip design, whose components include a GWAS

256k platform, an exome component (∼236k), and a

Psych component (∼50k). The platform was designed to

cheaply genotype large samples to identify robust asso-

ciations. The custom content covers common and rare

variants, CNVs, and community requests.

Dr Daniel Geschwind (UCLA, USA) presented a study

mapping SFARI and exome sequencing data of ASD to

developmental and anatomical data (developmental

dynamics and laminar specificity). Modules were found

to reflect important processes in cortical development.

Coexpression network showed clustering of genes

affected by de-novo mutation, and networks helped

stratify the more pathogenic variants. Transcriptional and

translational regulation was found to be linked to the

ASD modules. With respect to anatomical and circuit

specificity of ASD genes, a difference was recorded in

laminar enrichment of ASD-associated gene modules in

fetal human cortex and adult cortex. Function, expres-

sion, protein interaction, and regulation were all impli-

cated. Finally, ASD genes converged to disrupt neuronal

development and cortical–cortical connectivity in super-

ficial layers.

Stem cell science (reported by Hilary Akpudo)Dr Kevin Eggan (Harvard University, USA) highlighted

that new and emerging developments in stem cell

research have made it imperative that the architecture of

disease is reconceptualized. The hierarchical ways of

classifying disease fail to take into account new genetic

variations that are now known to underlie many neuro-

logic and psychiatric diseases. With the emergence of a

myriad of variants found in psychiatric patients with

autism and schizophrenia, two convergent models to

consider are the idea that (a) different mutations act

through distinct pathways with strong effects to cause



psychiatric disease and (b) that many small genetic var-

iants add up through convergent pathways to place

individuals into the psychiatric disease box. In either

case, we have to deploy models that have the flexibility

and capacity to take on board the study of many different

genetic variants in parallel. Stem cell reprogramming

approaches have presented new opportunities by allow-

ing an unprecedented supply of neuronal subtypes with

relevance to psychiatric disease and other conditions. If

done reproducibly and well, this promises to be an

important tool for dissecting the effects of these mono-

genic variants on human neurobiology. He reported that

with advances in stem cell biology and reprogramming

technology, it has become routine to use the cell-based

model of psychiatric disorders: fibroblast cells obtained

from patients can be used to generate live human neu-

rons with a genetic background known to produce the

disease state. First, fibroblasts can be reprogrammed to

hiPSCs by transient expression of OCT4, SOX2, KLF4,and c-MYC and then subsequently differentiated into

NPCs and mature neurons. Second, fibroblasts can be

directly converted into iNPCs by transient expression of

SOX2 and then subsequently differentiated to neurons.

Third, fibroblasts can be directly converted into a neu-

ronal fate by transient expression of ASCL1, BRN2,MYT1L, and NEUROD1. The real challenge for stem cell

science is how to responsibly deploy these types of

technologies to gain a durable understanding of the

genetic underpinnings of these conditions. He addressed

important questions about these technologies: (a) what

can in-vitro-derived cell types offer and what are the

liabilities of these systems? (b) Given that psychiatric

diseases affect select cell types in the brain, can the

correct cell types be produced rather than just generic

neurons in culture? (c) How reproducible can we

make the cell lines from patient to patient, from experi-

ment to experiment? What are the influences of these

reprogramming processes on the products made and

studied? When progenitor cells or human embryonic

stem cells are induced to differentiate into specific

neural populations for the study of disease, one problem

that every directed differentiation or lineage conversion

approach has is that none of them is neatly efficient in

making the type of cells we are interested in. The cell

subtype is embedded in a milieu of diverse cell types

from the nervous system. The relative proportion of

the desired cell type in the mixture is variable. One

approach to overcome this problem is to engineer stem

cell lines to carry reporter genes that allow those cells of

interest to be prospectively purified out of those more

diverse and complicated populations of cells. Cell line

variation in the study of psychiatric disease adds sub-

stantial ‘noise’ to phenotypic measures. This problem can

be overcome with gene targeting approaches, which

could also be useful in understanding the causal nature of

variants.

New mutations (reported by Lea K. Davis)Dr James R. Lupski (Baylor College of Medicine, Texas,

USA) spoke on the mechanisms for human genome

rearrangements. He described two major classes of rear-

rangement including recurrent and nonrecurrent events,

and highlighted the clinical importance of these

mechanisms. He noted that the postzygotic mosaic

mutation was 100–1000 times greater than the mutation

rate for SNVs. He described the mechanisms of non-

homologous end joining as well as fork stalling and

template switching, which is a replication-mediated

mechanism and can result in multiple complex rearran-

gements. He noted that CNVs can cause disease by

multiple mechanisms and that rare variants can con-

tribute toward common disease phenotypes.

Dr Jonathan Sebat (University of California, San Diego,

USA) spoke on using whole-genome sequencing to

identify hotspots for germline mutation in autism dis-

orders (ASDs). He presented the results of a study of 10

monozygotic twin families with ASDs. Five of the genes

discovered with germline mutations were also high-

lighted in recent autism exome studies. He then descri-

bed a metric constructed to quantify the mutability of

each base pair in the genome using genomic annotations

and the finding that genes associated with dominant

disorders have a higher mutability index.

Dr Steven A. McCarroll (Stanley Center for Psychiatric

Research, Broad Institute of MIT and Harvard, USA)

spoke on mutational hotspots and genetic analysis of

psychiatric illness. He described a study designed to

understand the relationship between replication timing

and mutational events. The first step of the study was to

grow cells asynchronously and then sort the mid S-phase

cells and compare genome-wide DNA dosage levels to

G1 cells (single diploid), thus constructing a map across

the genome to determine which regions replicate early

and which replicate late. They found that the timing of

replication events is synchronous across cells from a sin-

gle individual, but polymorphic across individuals. The

genetic variants controlling the timing events were then

mapped by GWAS. In addition, they then found that

transitions, transversions, and polymorphisms in general

were more common in late replicating regions of the

genome.

Dr Christopher A. Walsh (Boston Children’s Hospital)

spoke on somatic mutation and genomic diversity in the

developing human cerebral cortex. He presented results

from a study in which 300 single neurons from three

normal individuals were analyzed with multiple dis-

placement amplification and assessed for aneuploidy.

They found significant clonal mosaicism of

retrotransposon-mediated aneuploidy in the brain, which

can be mapped to a single neuronal source. These events

are unlikely to be a major source of neuronal diversity,

but in some cases, may be responsible for disease.



The future of psychiatric genetics: where dowe go from here? (reported by AlisonMerikangas)Drs Lynn DeLisi and Jordan Smoller (Harvard Medical

School, Boston, USA) introduced the session and the key

issues on the next steps for biological follow-up and

clinical translation of recent genetic discoveries.

Dr Patrick Sullivan (University of North Carolina, USA)

described that the primary goal of psychiatric genetics is

to discover underlying genetic and biologic pathways

rather than explaining heritability. He anticipated that

gaining understanding of the types and numbers of var-

iants, their mutual interactions, and the combined influ-

ence of environmental factors will be possible within the

next 3–10 years through both continued collaborative

efforts and application of multiple approaches in tandem,

such as examining common variation, structural variation,

exome sequencing, and whole-genome sequencing to

facilitate discovery.

Dr Peter Donnelly (Wellcome Trust Centre for Human

Genetics, Oxford, UK) explained the goals of studying

genetics including: (a) to learn key biology in an acces-

sible tissue; (b) to improve risk prediction; and (c) to

stratify the patient population, thereby refining the

diagnosis and improving treatments. He contrasted the

rate of discovery of common variants for schizophrenia

with those for Crohn’s disease, which required much

smaller samples, and how the latter led to the identifi-

cation of its key biologic pathways. Future research on

gene regulation and developmental timing, discovery of

relevant tissues, and their clinical relevance in terms of

drug targets on the basis of the direction of gene/pathway

modulation will be other important future directions.

There appears to be no relationship between GWAS

effect size and the potential as a drug target (e.g. statins).

Because there do not appear to be low-frequency variants

of large effect, and their lack of power, he questioned the

value of sequence-based discovery as it has not yet

yielded much information, especially in light of the high

cost. He supported efforts to mine large prospective

cohorts, such as the UK Biobank, in the future.

Dr Mark Daly (Massachusetts General Hospital and the

Broad Institute, USA) described the changing contribu-

tions of genetic findings to our understanding of the

underpinnings of disease, that they may deliver biological

insight that will be useful in therapeutic development. As

GWAS do not directly identify these pathways, advances

in high-throughput genomics, neurobiology, and identi-

fication of supportable models (human cells, fish, and

mice) to reverse the molecular change are needed. He

suggested that genome sequencing will provide an

opportunity to explore the genetic underpinnings of

psychiatric disorders and redirect efforts away from

noninformative findings. Genomics may also lead to

identification of distinct therapeutic subgroups as well as

in adverse drug reactions.

Dr Thomas Insel (Director of The National Institute of

Mental Health, USA) described multiple ongoing and

future directions for genomics research including: (a) the

continued use of large samples; (b) studies of gene

expression (e.g. the Genetic Tissue Expression project of

> 900 individuals with 32 tissue types exploring variation

in tissue expression); (c) developments in iPSC tech-

nology and model animal studies; (d) identification of

environmental effects on gene expression; (e) studies

that identify phenotypes on the basis of genotypes, par-

ticularly rare variants; (f) studies of resilient populations;

and (g) studies examining developmental patterns of

gene expression (e.g. the BrainSpan project). He

emphasized that all of these directions will rely on shar-

ing, standardizing, and integrating data.

Issues addressed in discussion: (a) the need to expand

studies to other (non-European) ancestries; (b) dis-

agreement on whether identification of a large number of

genetic markers of small effect can be considered a suc-

cess; (c) the importance of replication before moving

forward with labor-intensive biologic studies; and (d) the

importance of identifying environmental risk factors. The

difficulties in consortia models were discussed in terms of

consent and attribution of scientific contributions.

The 2013 Snow and Ming Tsuang lifetime achievement

award winner: John I. Nurnberger Jr (Indiana University

School of Medicine, USA) (reported by Leon M.

Hubbard)

Dr Nurnberger’s work has contributed considerably

toward the genetics and neurobiology of BPD, AD, and

autism/autistic spectrum disorders (ASDs). He presented

a fascinating journey through 20th-century and 21st-

century psychiatric genetics, with an emphasis on the

advances in BPD. He spoke about his psychiatric resi-

dency at the New York State Psychiatric Institute in the

1970s, where his interest in BPD developed through

working with Professor David Dunner (University of

Washington), who defined bipolar II and rapid cycling

subtypes. His mentor, Elliot Gershon (University of

Chicago), introduced him to methodological design of

family, linkage, and association studies that would

become pivotal in his career. Reflecting on research

performed with Gershon and colleagues on the neuro-

biology of BPD in the 1980s, Professor Nurnberger spoke

about the novel paradigms used to study cholinergic

rapid eye movement sleep in euthymic bipolar patients

(Sitaram et al., 1980) and super sensitivity to light being a

potential trait of BPD (Lewy et al., 1985), among others.

These studies investigated interesting hypotheses, but

he reflected that they had problems of scalability, and

could not overcome problems of disease heterogeneity

and other confounding factors such as medication effects.

The development of consortia has helped to overcome

some of the limitations observed in smaller scale studies

in the 1980s. Professor Nurnberger is a member of



COGA, the Autism Genome Project, the Bipolar

Genome Study, and Bipolar High Risk Consortium.

Furthermore, he discussed his involvement with the

PGC Bipolar Working Group that found genome-wide

association for rs1006737 in CACNA1C. Enrichment was

observed for the gene ontology category ‘voltage gated

calcium channel activity’ including calcium channel

genes CACNA1D and CACNB3 (Psychiatric GWAS

Consortium Bipolar Disorder Working Group, 2011). A

recent meta-analysis of individuals with schizophrenia,

BPD, major depression, autism, and ADHD showed

enrichment for calcium channel genes across these dis-

orders [Cross-Disorder Group of the Psychiatric

Genomics Consortium; Genetic Risk Outcome of

Psychosis (GROUP) Consortium, 2013]. Calcium chan-

nel antagonist flunarizine has shown antipsychotic prop-

erties in schizophrenia (Bisol et al., 2008); however, singlestudies lack consistency, with further work required to

translate the observed enrichment of calcium channel

genes into efficacious treatments (Casamassima et al.,2010). In conclusion, Professor Nurnberger compared the

myriad of new genetic findings across psychiatric diseases

with a good harvest after the summer rains. He instilled

the importance of utilizing technological innovation and

collaboration to further understand the genetic etiology

and neurobiology of psychiatric disorders.

AcknowledgementsThis report was made possible by grants from NIMH and

NIDA: R13MH060596 and R13DA022792. Each sum-

mary is the subjective understanding of the rapporteur for

each session. The data reported are as heard during the

presentation and where possible; all statements have

been checked with the speaker for accuracy. However,

the speakers are not responsible for any of the informa-

tion contained in this report.

Conflicts of interest

There are no conflicts of interest.

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