Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
4 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 5
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
6 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
XXI World Congress of Psychiatric Genetics Akpudo et al. 7
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
(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.
8 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 9
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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-
10 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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;
XXI World Congress of Psychiatric Genetics Akpudo et al. 11
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
12 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
XXI World Congress of Psychiatric Genetics Akpudo et al. 13
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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,
14 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 15
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
16 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 17
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
18 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 19
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
20 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 21
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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.
22 Psychiatric Genetics 2014, Vol 00 No 00
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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
XXI World Congress of Psychiatric Genetics Akpudo et al. 23
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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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