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Figure.
Mean Schizophrenia Profile Scores From Genomic Best Linear Unbiased Prediction (GBLUP) in Community Samples of Women (No Ascertainment Based on Psychiatric Disorders) Grouped by Age at Birth of Their First Child
Mean Schizophrenia Profile Scores From Genomic Best Linear Unbiased Prediction (GBLUP) in Community Samples of Women (No Ascertainment Based on Psychiatric Disorders) Grouped by Age at Birth of Their First Child

The error bars are SEs.

Table 1.  
Sample Size and Age at First Birth Across 4 Cohorts
Sample Size and Age at First Birth Across 4 Cohorts
Table 2.  
Coefficients of Determination and P Valuesa
Coefficients of Determination and P Valuesa
Supplement.

eAppendix 1. Data

eAppendix 2. Profile Score Method

eAppendix 3. Consortia Members

eTable 1. Characteristics of the PGC2-SCZ Cohorts Used in the Current Analysis

eTable 2. P-value Testing Significance Difference of Profile Score From GBLUP Analysis Between AFB Groups

eTable 3. The Coefficient of Determination (R2) and P-value When Using Either the Model 1 and Model 2 Variables as the Dependent Variables in Regression on Risk Profile Scores From GBLUP Based on the Total Sample of 12 247 Women

eTable 4. The Coefficient of Determination (R2) and P-value When Using Either the Model 1 and Model 2 Variables as the Dependent Variables in Regression on Risk Profile Scores From the GWAS Summary Statistics

eTable 5. The Coefficient of Determination (R2) and P-value When Using Either the Model 1 and Model 2 Variables as the Dependent Variables in Regression on Risk Profile Scores From GBLUP When Using Women Aged 45 Years or Over at Recruitment Including Women Having No Child (No AFB)

eTable 6. The Coefficient of Determination (R2) and P-value When Using Either the Model 1 and Model 2 Variables as the Dependent Variables in Regression on Risk Profile Scores From GBLUP for Each Individual Cohort

eTable 7. The Coefficient of Determination (R2) and P-value When Using Either the Model 1 and Model 2 Variables as the Dependent Variables in Regression on Risk Profile Scores From GBLUP When Using Subsample Born Before or After the Year 1945

eTable 8. The Coefficient of Determination (R2) and P-value When EA Profile Was Additionally Used to Adjust AFB

eFigure 1. Distribution of AFB Across the 4 Cohorts

eFigure 2. Distribution of Year of Birth for the AFB Sample Across the 4 Cohorts

eFigure 3. Polynomial Function (Model 1) Derived From Incidence Rate Ratio for Schizophrenia by Maternal Age From McGrath et al. (2014)

eFigure 4. Polynomial Function (Model 2) Derived From Incidence Rate Ratio for Schizophrenia by Maternal Age Adjusted for Age of Other Parent and Urbanization of Place of Birth From McGrath et al. (2014)

eFigure 5. Mean Profile Scores From GWAS Summary Statistics With Women Grouped by Age at Birth of Their First Child

eFigure 6. Mean Profile Scores From GBLUP Analysis of Women Grouped by Age at Birth of Their First Child for Each Cohort

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Original Investigation
May 2016

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women

Author Affiliations
  • 1Queensland Brain Institute, The University of Queensland, Brisbane, Australia
  • 2Department of Sociology, Interuniversity Center for Social Science Theory and Methodology, University of Groningen, Groningen, the Netherlands
  • 3Department of Sociology, Nuffield College, University of Oxford, Oxford, England
  • 4Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond
  • 5Department of Psychiatry, Virginia Commonwealth University, Richmond
  • 6Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England
  • 7Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 8Estonian Genome Center, University of Tartu, Tartu, Estonia
  • 9Department of Epidemiology, University of Groningen, The University Medical Center Groningen, Groningen, the Netherlands
  • 10Queensland Centre for Mental Health Research, Wacol, Australia
  • 11Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond
  • 12School of Environmental and Rural Science, University of New England, Armidale, Australia
JAMA Psychiatry. 2016;73(5):497-505. doi:10.1001/jamapsychiatry.2016.0129
Abstract

Importance  A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age.

Objective  To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets.

Design, Setting, and Participants  This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study.

Main Outcomes and Measures  We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father’s age.

Results  We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014.

Conclusions and Relevance  This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

Introduction

Parental age is a risk factor for a range of adverse mental health outcomes in children, including common psychiatric disorders, such as schizophrenia (SCZ).13 Advanced paternal age has received the most attention, with risk to children widely assumed to be explained by de novo mutations that occur more frequently in the germline of older men,46 although other studies7,8 question the de novo mutation hypothesis. There is also emerging evidence to suggest that children of both younger9 and older10 mothers are at increased risk of psychosis.

One recent major study is by McGrath et al,11 who performed a comprehensive analysis using family data extracted from the Danish Psychiatric Central Register and reported a U-shaped relationship between maternal age and risk of SCZ in offspring. They showed that there was higher risk in children of younger and older mothers compared with those of intermediate age (25-29 years). In their secondary analyses that were adjusted for the age of the father, which tends to be highly correlated with mother’s age, increased risk of SCZ was associated with younger mothers (<25 years) but not older mothers. Conversely, children of older fathers (>29 years) were at increased risk, even after correcting for the age of the mother, but children of younger fathers were not. These epidemiological findings for the association of maternal age and risk of SCZ cannot dissect cause from consequence. That is, it is unclear if risk to offspring is due to psychosocial, lifestyle, or biological aging factors associated with maternal age or if women at higher risk for SCZ tend, on average, to have their first child at an earlier or later age. Herein, our analyses use a novel design to explore the relationship between age at motherhood and SCZ.

Recently developed whole-genome analysis methods provide an opportunity to investigate this question in a novel way that is independent of potential confounding factors. Genomic relationships and risk profile scores on unrelated individuals derived from genome-wide single-nucleotide polymorphism (SNP) data can be used to dissect the shared genetic architecture of complex traits.12 For instance, independently collected unrelated individuals can be linked through genomic information, correlating their genotype sharing with similarities in their phenotypes. Because the individuals who are compared are not related in the conventional sense, any covariance between their shared genome and their phenotype is most likely genetic and likely free of confounding environmental effects. This novel design enables the use of independent genome-wide association study (GWAS) data sets to quantify the extent of genetic overlap across complex traits.

Herein, we investigated the genetic relationship between SCZ and age at first birth (AFB) in women using multiple independent GWAS data sets. Specifically, we used genetic risk alleles and their effect sizes estimated from SCZ GWAS data to create a genetic SCZ risk profile score for each woman in the AFB data set. The AFB data set comprises community samples of women (ie, not ascertained for psychiatric disorders) who had their age at birth of their first child recorded. While both SCZ and AFB are heritable traits,1315 here the genetic contribution underpinning the trait age at first motherhood is not dependent on the age of her partner. We tested if the relationship between a woman’s AFB and her SCZ risk profile score matched that reported by McGrath et al11 between the age of mothers and the incidence rate ratio (IRR) for SCZ in their children.

Box Section Ref ID

Key Points

  • Question Is there a genetic association between schizophrenia (SCZ) and age at first birth (AFB) in women?

  • Findings In the analyses, the SCZ genome-wide association study (GWAS) comprised 18 957 cases and 22 673 controls, and the AFB GWAS comprised 12 247 women. Using these multiple independent GWAS data sets, we found a significant genetic association between SCZ risk and AFB.  

  • Meaning SCZ risk in offspring associated with early and delayed maternal age is partly explained by the genetic association between SCZ and AFB

Methods

Each study obtained ethical board approval and written informed consent from all participants (eAppendix 1 in the Supplement). The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a GWAS from the second phase of the Psychiatric Genomics Consortium (PGC2-SCZ),15 and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK) (eAppendix 1 in the Supplement contains full details). These community cohorts measured for AFB were not enriched for psychiatric disorders. We used genomic best linear unbiased prediction (GBLUP), implemented in the MTG software,16 to estimate SNP effects in our quality-controlled PGC2-SCZ data set (n = 41 630) (eTable 1 in the Supplement lists sample details). Briefly, SNP effects were estimated jointly within a linear mixed model that intrinsically accounts for linkage disequilibrium between SNPs. In estimating SNP effects, we fitted sex, cohort, and 20 ancestry principal components obtained from the sample to control for potential confounding effects, such as population stratification and potential batch effects. The SNP risk predictors were projected into the AFB samples, resulting in a GBLUP risk profile score for each individual. We repeated our analyses using standard genetic risk profile scores17,18 (eAppendix 2 in the Supplement), in which the SCZ risk scores in the women measured for AFB were estimated by summing the count of the SCZ risk alleles weighted by their effect sizes (log[odds ratio]) estimated from our quality-controlled SCZ GWAS data. A regression of phenotype on genetic risk profile score tests for association between the measures. The GBLUP risk profile score is expected to be more accurate than a standard risk profile score because the available data in the SCZ sample are used more optimally in the GBLUP linear mixed-model methodology. In particular, arbitrary decisions about P value and linkage disequilibrium clumping that are inherent in standard profile scoring are avoided.

The distribution of AFB and year of birth for each cohort are summarized in Table 1 and eFigure 1 and eFigure 2 in the Supplement. In analyses for AFB, we generated 2 response variables using polynomial functions derived from McGrath et al11 to describe the relationship between IRR for SCZ in offspring and maternal age (model 1 [2.7214 + 0.0018x2 − 0.1105x]) or maternal age adjusted for the age of the other parent and urbanization of the place of birth (model 2 [2.5438 + 0.0012x2 − 0.0889x]). eFigure 3 and eFigure 4 in the Supplement show how we derived the polynomial functions. In generating the model 1 and model 2 values for each individual, AFB was used as the x variable in the equations. In analyses, we used the residuals of the model 1 or model 2 values after regression on covariates, such as age at interview, 20 ancestry principal components, and cohort. We did not include year of birth as a covariate because its negative value was highly correlated with age at interview (>0.9). The fitted residuals were regressed against risk profile scores, and we report the proportion of variance (R2) attributable to the polygenic score. The P value results from the test of the hypothesis R2 = 0. The purpose of these analyses was to test if the SCZ polygenic risk values are a better fit to the phenotypic risk values predicted by model 1 or model 2. A smaller P value for model 1 would imply a better fit to the AFB data compared with model 2, for which the linear and quadratic coefficients were derived from models that adjusted for the age of the partner. Analyses were performed for the entire AFB sample and for subsets of women stratified by the mean AFB (26 years) into younger AFB (<26 years) and older AFB (≥26 years).

Results

We sought to provide insight to the relationship between maternal age and SCZ by exploring genetic overlap between SCZ risk in women measured for AFB. We observed a U-shaped relationship between AFB and SCZ risk profile scores derived using GBLUP (Figure), consistent with the relationship reported by McGrath et al11 between SCZ risk in offspring and maternal age not adjusted for the father’s age. The mean risk profile score from GBLUP analysis was significantly higher in women with early AFB (ie, <20 years) than in women with intermediate AFB (P = 8.8E-03 for AFB of 25 to <30 years and P = 1.3E-02 for AFB of 30 to <35 years) (eTable 2 in the Supplement). The results from standard profile score were very similar to those from GBLUP but showed weaker signals (eFigure 5 and eFigure 6 in the Supplement).

We further investigated if SCZ genetic risk profiles significantly predicted the model 1 or model 2 response variables, which are the phenotypic predictors of SCZ risk derived from the results reported by McGrath et al11 (Table 2). We initially focused on a subsample of women 45 years or older at recruitment (n = 10 836) to avoid any potential bias owing to the inclusion of women who were childless at recruitment but still of childbearing age. In analyses of the full range of AFB in this sample, the model 1 and model 2 response variables were strongly predicted by GBLUP-derived SCZ risk profile scores (P = 4.1E-04 and P = 5.0E-03 for model 1 and model 2, respectively). The smaller P value for model 1 implies a better fit to the AFB data compared with model 2, which is consistent with the suggestion that adjusting for paternal age removes a true association between maternal age and IRR for SCZ. When restricting the analysis to younger mothers whose AFB was less than the mean (AFB <26 years), the P values were P = 6.2E-04 and P = 5.1E-04 for model 1 and model 2, respectively. On the other hand, assessing only older mothers (AFB ≥26 years), GBLUP profile score weakly predicted model 1 (P = 1.4E-02) but not model 2 (P = 2.5E-01). We repeated the analyses using the total sample of 12 247 women and found almost identical results (eTable 3 in the Supplement), suggesting very little if any bias arising from the inclusion of an additional 1411 women younger than 45 years at recruitment. Again, analyses based on the profile score approach gave similar but weaker significance than GBLUP (eTable 4 in the Supplement).

In our primary analyses, we excluded women without children because the appropriate way to include such women in our analyses is difficult to determine. Delayed AFB and childlessness might have a common genetic predisposition or might be on distinct dimensions of liability. To explore this, we repeated the analyses with the inclusion of women having no children, whose age at recruitment was 45 years or older. In this analysis, we assigned women having no children an AFB of 45 years, which has been reported as the end of reproductive age.19 Both response variables were predicted in analyses across the full range of AFB; however, the significance of the prediction was considerably decreased, and neither response variable was predicted in analyses of women with AFB of 26 years or older (eTable 5 in the Supplement). These results must be interpreted with caution because there could be many reasons why women have no children, with the most common being infertility, which is likely to be genetically independent of AFB among those able to conceive.

In addition to analyses of the total AFB sample, we examined the relationship between SCZ risk profile scores from GBLUP and the model 1 and model 2 response variables in each cohort (eTable 6 in the Supplement), acknowledging that owing to smaller sample size the power to detect a relationship was substantially reduced. For Estonian Genome Center Biobank, University of Tartu, risk profile scores were not significantly associated with AFB (see the Discussion section). However, a significant association remained in the other cohorts for at least 1 response variable. The prediction for the LifeLines Cohort Study was significant for model 1 when using the whole range of AFB or AFB younger than 26 years. For the Swedish Twin Registry, it was significant only for model 1 in analyses of women with AFB of 26 years or older. For TwinsUK, both response variables were predicted in analyses of the full range of AFB and AFB younger than 26 years but not in analyses of women with AFB of 26 years or older (eTable 6 in the Supplement). Due to smaller sample size, the U-shaped relationship observed between SCZ risk and AFB was less apparent in each cohort.

We stratified the AFB sample into birth cohorts born before or after 1945, a demarcation based on the second demographic transition that is linked in the literature to postponement of AFB.20 For individuals born after 1945, SCZ risk profile scores from GBLUP significantly predicted AFB for the entire sample and the younger AFB group but not for the older AFB group (eTable 7 in the Supplement). For individuals born before 1945, SCZ risk profile scores from GBLUP did not significantly predict AFB.

Discussion

Maternal age is a risk factor for a number of adverse mental health outcomes, including common psychiatric disorders, such as SCZ.21,22 In a recent study, McGrath et al11 reported a U-shaped relationship between maternal age and risk of SCZ in children, although in analyses corrected for the age of the other parent only children of younger mothers were at increased risk. Their study implied that risk of SCZ in children of older mothers was attributable to the father’s age, consistent with the hypothesis of risk arising from paternal age-related de novo mutations and the presence of a strong correlation between maternal and paternal age. However, because a larger proportion of older men have younger partners than is the case for older women, there is a possibility that correcting for the age of the spouse may remove a true effect due to advanced maternal age. In other words, the well-known problem of collinearity,2325 which can lead to biased estimates for explanatory variables that are adjusted for a correlated variable (eg, maternal age adjusted for paternal age), may result in an underestimate of the risk due to older maternal age in analyses, such as that reported by McGrath et al.11 Our study uses a novel experimental design that is free of effects of the partner’s age; therefore, there is no concern about such a collinearity problem in our analyses.

Maternal age is a proxy for factors other than parental age, including de novo chromosomal abnormalities, and psychosocial factors related to socioeconomic status and educational attainment, both of which are associated with risk of SCZ. Conversely, relatives of individuals affected with SCZ tend to have poor social interactions,26 which may increase the time taken to find a mate and thereby delay AFB. Schizophrenia risk may also predispose to risk taking and impulsive behavior, which is associated with early pregnancy and childbirth in women.2729 Consequently, risk of SCZ in offspring due to maternal AFB may be influenced by shared genetic factors between mothers and offspring, as has been suggested for paternal AFB.7,8

In this study, we investigated genetic overlap between SCZ and AFB using a novel experimental design based on genomic data that enables genetic effects to be disentangled from other confounding factors. This is achieved through independently collected SCZ and AFB data sets that are genetically informative. The AFB data are collected from community samples with no known enrichment for psychiatric disorders. In particular, we sought to determine if response variables based on the relationships reported by McGrath et al11 between maternal age and SCZ risk in children (model 1 and model 2) could be predicted by SCZ risk profile scores in our independent data. We found that SCZ risk profile scores predicted both model 1 and model 2, implying that polygenic variation for SCZ contributes to the relationships reported by McGrath et al11 between maternal age and risk of SCZ.

Our results were stronger for the U-shaped model 1 response variable (based on unadjusted IRR) than model 2 (in which IRR was adjusted for paternal age and urbanization of the place of birth), suggesting that polygenic variation contributes to risk of SCZ associated with both early and delayed maternal AFB. In analyses stratified by the mean AFB, evidence for genetic overlap between SCZ and AFB was strongest in women with early AFB (<26 years). In analyses of women with delayed AFB (≥26 years), we observed an association with the SCZ risk profile score but only for the model 1 response based on unadjusted IRR. Given that our methodology explores the relationship between AFB genetic risk and SCZ in a way that is independent of correlation between the ages of the parents, our analyses suggest that risk of SCZ in children of older mothers is not solely attributable to factors associated with advanced paternal age.

A caveat of our findings is that the genetic association between risk of SCZ and delayed AFB was only marginally significant given the number of analyses performed, perhaps reflecting smaller sample size and correspondingly larger standard errors for women with delayed AFB, and so require replication in a larger sample. Provided that this finding is confirmed in a future study, it has important implications because it implies that risk of SCZ associated with increased age in mothers is not entirely due to the father’s age.

Although we demonstrate that SCZ genetic risk can be disentangled from psychosocial, lifestyle, and biological aging factors in assessing the relationship between SCZ risk and AFB, we cannot explicitly determine mechanism, and it is possible that subtle correlations between genetic and nongenetic factors might influence this relationship. Several mechanisms, such as correlation of SCZ risk with socioeconomic status and other environmental and biological factors, might also influence the genetic relationship between SCZ and AFB. For instance, SCZ risk could predispose to impulsive behavior29 and substance use,27 which are associated with early pregnancy and childbirth.28 On the other hand, poor social competence in SCZ might delay the time to meet a partner or have offspring, causing delayed AFB. Other plausible mechanisms, such as low IQ and poor educational attainment, which are strong risk factors for both SCZ30 and early pregnancy,21 need to be explored, although the inclusion of the genetic profile score for educational attainment as a covariate had little impact on our results (eTable 8 in the Supplement). Assessing these factors is beyond the scope of this study. Future research that includes social science measures and information on nongenetic factors will facilitate a deeper understanding of causal pathways underlying the association between SCZ and AFB.

The analyses by McGrath et al11 explored the relationship between parental age and a broad range of psychiatric disorders. Herein, we have only considered genetic risk for SCZ because sample size, and hence the power to estimate risk allele effect sizes, is greatest. For example, 108 independent risk loci for SCZ have been identified as being genome-wide significant15 compared with only 3 for bipolar disorder.31 As GWAS sample sizes for other psychiatric disorders increase, then replication of our analyses based on these disorders will be possible.

Conclusions

In summary, this study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. To our knowledge, this is the first study to explore a genetic relationship between SCZ and AFB using independent unrelated samples based on genomic data. We conclude that women with high genetic predisposition to SCZ tend to have their first child at an early age or a later age compared with women in the general population.

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Article Information

Submitted for Publication: September 17, 2015; final revision received November 24, 2015; accepted January 11, 2016.

Corresponding Author: S. Hong Lee, PhD, School of Environmental and Rural Science, University of New England, Armidale, New South Wales, Australia 2351 (hong.lee@une.edu.au).

Published Online: March 23, 2016. doi:10.1001/jamapsychiatry.2016.0129.

The Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK Consortium Authors include Ole A. Andreassen, MD, PhD; Elvira Bramon, MD, PhD; Richard Bruggeman, MD, PhD; Joseph D. Buxbaum, PhD; Murray J. Cairns, PhD; Rita M. Cantor, PhD; C. Robert Cloninger, MD, PhD; David Cohen, MD, PhD; Benedicto Crespo-Facorro, MD, PhD; Ariel Darvasi, PhD; Lynn E. DeLisi, MD; Timothy Dinan, MD, PhD; Srdjan Djurovic, PhD; Gary Donohoe, PhD; Elodie Drapeau, PhD; Valentina Escott-Price, PhD; Nelson B. Freimer, MD; Lyudmila Georgieva, PhD; Lieuwe de Haan, MD, PhD; Frans A. Henskens, BMath, DipEd, DipCompSc, PhD; Inge Joa, PhD; Antonio Julià, PhD; Andrey Khrunin, PhD; Bernard Lerer, MD; Svetlana Limborska, PhD; Carmel M. Loughland, BA (Hons), PhD; Milan Macek Jr, MD, PhD; Patrik K. E. Magnusson, PhD; Sara Marsal, MD, PhD; Robert W. McCarley, MD; Andrew M. McIntosh, MD, FRCPsych; Andrew McQuillin, PhD; Bela Melegh, MD, PhD, DSc; Patricia T. Michie, PhD; Derek W. Morris, PhD; Kieran C. Murphy, MD, PhD; Inez Myin-Germeys, PhD; Ann Olincy, MD; Jim Van Os, MD, PhD; Christos Pantelis, MD, Hon MD (Athens), MRCPsych, FRANZCP; Danielle Posthuma, PhD; Digby Quested, MBChB, MD, FRCPsych; Ulrich Schall, MD, FRANZCP, PhD, DSc; Rodney J. Scott, PhD, FRCPath, FHGSA, FFSc; Larry J. Seidman, PhD; Draga Toncheva, MD, PhD, DSc; Paul A. Tooney, PhD; John Waddington, PhD, DSc; Daniel R. Weinberger, MD; Mark Weiser, MD; Jing Qin Wu, PhD.

Affiliations of The Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK Consortium Authors: NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (Andreassen); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (Andreassen); University College London, London, England (Bramon); University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, the Netherlands (Bruggeman); Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, New York (Buxbaum); Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York (Buxbaum); Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York (Buxbaum); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York (Buxbaum, Drapeau); Schizophrenia Research Institute, Sydney, Australia (Cairns, DeLisi, Henskens, Loughland, Michie, Pantelis, Schall, Scott, Tooney, Wu); Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia (Cairns, Loughland, Schall); School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, Australia (Cairns, Scott, Tooney, Wu); Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles (Cantor); Department of Psychiatry, Washington University in St Louis, St Louis, Missouri (Cloninger); Department of Child and Adolescent Psychiatry, Assistance Publique Hôpitaux de Paris, Pierre and Marie Curie University, and Institute for Intelligent Systems and Robotics, Paris, France (Cohen); CIBERSAM, University Hospital Marqués de Valdecilla, University of Cantabria–IDIVAL, Department of Psychiatry, Santander, Spain (Crespo-Facorro); Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain (Crespo-Facorro); Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel (Darvasi); VA Boston Health Care System, Brockton, Massachusetts (DeLisi, McCarley); Department of Psychiatry, University College Cork, Cork, Ireland (Dinan); NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway (Djurovic); Department of Medical Genetics, Oslo University Hospital, Oslo, Norway (Djurovic); Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland (Donohoe, Morris); Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland (Donohoe, Morris); MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, Wales (Escott-Price, Georgieva); Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (Freimer); Department of Psychiatry, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands (de Haan); School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, Australia (Henskens); Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, Australia (Henskens); Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway (Joa); Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain (Julià, Marsal); Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia (Khrunin, Limborska); Department of Psychiatry, Hadassah–Hebrew University Medical Center, Jerusalem, Israel (Lerer); Department of Biology and Medical Genetics, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic (Macek); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Magnusson); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (McCarley, Seidman); Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland (McIntosh); Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland (McIntosh); Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, England (McQuillin); Department of Medical Genetics, University of Pécs, Pécs, Hungary (Melegh); Szentagothai Research Center, University of Pécs, Pécs, Hungary (Melegh); School of Psychology, University of Newcastle, Newcastle, Australia (Michie); Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland (Murphy); Center for Contextual Psychiatry, Department of Neuroscience, KU Leuven, Leuven, Belgium (Myin-Germeys); Department of Psychiatry, University of Colorado Denver, Aurora (Olincy); Institute of Psychiatry, King’s College London, London, England (Van Os); Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, the Netherlands (Van Os); Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Melbourne, Australia (Pantelis); Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands (Posthuma); Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, the Netherlands (Posthuma); Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, the Netherlands (Posthuma); Department of Psychiatry, University of Oxford, Oxford, England (Quested); Hunter New England Health Service, Newcastle, Australia (Scott); Massachusetts Mental Health Center Public Psychiatry Division, Beth Israel Deaconess Medical Center, Boston (Seidman); Department of Medical Genetics, Medical University, Sofia, Bulgaria (Toncheva); Priority Research Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia (Tooney); Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland (Waddington); Lieber Institute for Brain Development, Baltimore, Maryland (Weinberger); Department of Psychiatry and Behavioral Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland (Weinberger); Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, Maryland (Weinberger); Department of Neuroscience, The Johns Hopkins School of Medicine, Baltimore, Maryland (Weinberger); Institute of Genetic Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland (Weinberger); Sheba Medical Center, Tel Hashomer, Israel (Weiser).

Author Contributions: Drs Mehta and Lee had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wray, Lee, Crespo-Facorro, Dinan, Schall, Weinberger.

Acquisition, analysis, or interpretation of data: Mehta, Tropf, Gratten, Bakshi, Zhu, Hemani, Magnusson, Esko, Metspalu, Snieder, Kendler, McGrath, Mills, Wray, Lee, Andreassen, Bramon, Bruggeman, Buxbaum, Cairns, Cantor, Cloninger, Cohen, Crespo-Facorro, Darvasi, DeLisi, Djurovic, Donohoe, Drapeau, Escott-Price, Freimer, Georgieva, de Haan, Henskens, Joa, Julià, Khrunin, Lerer, Limborska, Loughland, Macek, Magnusson, Marsal, McCarley, McIntosh, McQuillin, Melegh, Michie, Morris, Murphy, Myin-Germeys, Olincy, Van Os, Pantelis, Posthuma, Quested, Scott, Seidman, Toncheva, Tooney, Waddington, Weinberger, Weiser, Wu.

Drafting of the manuscript: Mehta, Tropf, Gratten, Kendler, Wray, Lee, Crespo-Facorro, DeLisi, Donohoe, Tooney.

Critical revision of the manuscript for important intellectual content: Mehta, Tropf, Gratten, Bakshi, Zhu, Bacanu, Hemani, Magnusson, Barban, Esko, Metspalu, Snieder, Mowry, Kendler, Yang, Visscher, McGrath, Mills, Wray, Lee, Andreassen, Bramon, Bruggeman, Buxbaum, Cairns, Cantor, Cloninger, Cohen, Crespo-Facorro, Darvasi, Dinan, Djurovic, Drapeau, Escott-Price, Freimer, Georgieva, de Haan, Henskens, Joa, Julià, Khrunin, Lerer, Limborska, Loughland, Macek, Magnusson, Marsal, McCarley, McIntosh, McQuillin, Melegh, Michie, Morris, Murphy, Myin-Germeys, Olincy, Van Os, Pantelis, Posthuma, Quested, Schall, Scott, Seidman, Toncheva, Waddington, Weinberger, Weiser, Wu.

Statistical analysis: Mehta, Lee, Escott-Price.

Obtained funding: Wray, Lee, Bramon, Djurovic, Henskens, McIntosh, Michie, Morris, Murphy, Pantelis, Posthuma, Schall, Scott.

Administrative, technical, or material support: Mehta, Tropf, Gratten, Bakshi, Zhu, Bacanu, Hemani, Magnusson, Barban, Esko, Metspalu, Snieder, Mowry, Kendler, Yang, Visscher, McGrath, Mills, Wray, Lee, Bramon, Bruggeman, Buxbaum, Cairns, Cloninger, Darvasi, Donohoe, Henskens, Julià, Khrunn, Lerer, Limborska, Loughland, Magnusson, Marsal, McIntosh, McQuillin, Melegh, Morris, Olincy, Van Os, Schall, Seidman, Toncheva, Waddington, Wu.

Study supervision: Lee, Dinan, Murphy, Quested, Schall, Weinberger.

Conflict of Interest Disclosures: None reported.

Funding/Support: This research is supported by grants 613602, 1047956, 1078901, 1080157, 1087889, and 1067795 from the Australian National Health and Medical Research Council and by grants DE130100614 and DP160102126 from the Australian Research Council. Primary analyses of the Schizophrenia Working Group of the Psychiatric Genomics Consortium data were conducted on the Genetic Cluster Computer (http://www.geneticcluster.org) hosted by SURFsara and supported by grant NOW 480-05-003 from the Netherlands Scientific Organization, along with a supplement from the Dutch Brain Foundation and the Vrije Universitiet Amsterdam. TwinsUK was funded by the Wellcome Trust, by grant FP7/2007-2013 from the European Community’s Seventh Framework Programme, and by support from the National Institute for Health Research–funded BioResource, Clinical Research Facility, and Biomedical Research Centre based at Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London, and single-nucleotide polymorphism genotyping was performed by the Wellcome Trust Sanger Institute and National Eye Institute via the National Institute for Health/Center for Inherited Disease Research. Estonian Genome Center Biobank, University of Tartu, received targeted financing by grant IUT20-60 from the Estonian Research Council, Center of Excellence in Genomics, and University of Tartu, and data analyses were carried out in part in the High Performance Computing Center of the University of Tartu. The Swedish Twin Registry is supported by Karolinska Institutet. Mr Tropf received funding from sciencestarter.de for a research visit to The University of Queensland. The research leading to these results received funding from the European Research Council via an ERC Consolidator Grant SOCIOGENOME (grant 615603 awarded to Dr Mills [http://www.sociogenome.com]).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Availability Statement: This study was conducted through approved data analysis applications made to the consortia involved. For ethical and legal reasons, we are not allowed to distribute them. The data of the Schizophrenia Working Group of the Psychiatric Genomics Consortium can be accessed through secondary analysis proposals (http://www.med.unc.edu/pgc/documents/documents-for-investigators#access). The LifeLines Cohort Study data are available by contacting the LifeLines Research Office (LLscience@umcg.nl) (https://www.lifelines.nl/lifelines-research/general). The data cannot be released without assessment by the LifeLines Scientific Committee with transfer agreements because the phenotypic data can be sensitive and have the potential in some cases to lead to the identification of individuals involved in the study. These procedures have been put in place by the LifeLines Scientific Board and local ethic committees. For more information, see the following article: Scholtens S, Smidt N, Swertz MA, et al. Cohort profile: LifeLines, a three-generation cohort study and biobank. Int J Epidemiol. 2015;44(4):1172-1180. Medline:25502107. TwinsUK data are available on request by contacting the Twin Research Unit (http://www.twinsuk.ac.uk/data-access) submission procedure. The data cannot be released without assessment by a steering committee with transfer agreements because the phenotypic data can be sensitive and may in some cases lead to the identification of the twins involved in the study. These procedures have been put in place by the local ethics committee and the Wellcome Trust.

Group Information: The Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK consortium collaborators are as follows: Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden (Rolf Adolfsson, MD, PhD, and Annelie Nordin, PhD); NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (Ingrid Agartz, MD, PhD, Erik G. Jönsson, MD, PhD, Morten Mattingsdal, MS, and Ingrid Melle, MD, PhD); Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway (Ingrid Agartz, MD, PhD); Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden (Ingrid Agartz, MD, PhD); State Mental Hospital, Haar, Germany (Margot Albus, MD); Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California (Madeline Alexander, PhD, Claudine Laurent, MD, PhD, and Douglas F. Levinson, MD); Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia (Farooq Amin, MD); Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia (Farooq Amin, MD); Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond (Silviu A. Bacanu, PhD, Tim B. Bigdeli, PhD, and Brandon K. Wormley, BA); Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany (Martin Begemann, MD, Hannelore Ehrenreich, MD, DVM, Christian Hammer, PhD, and Sergi Papiol, PhD); Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts (Richard A. Belliveau Jr, BA, Elizabeth Bevilacqua, BS, Kimberley D. Chambert, MSc, Giulio Genovese, PhD, Steven A. McCarroll, PhD, Jennifer L. Moran, PhD, and Edward M. Scolnick, MD); Department of Medical Genetics, University of Pécs, Pécs, Hungary (Judit Bene, PhD); Szentagothai Research Center, University of Pécs, Pécs, Hungary (Judit Bene, PhD); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (Sarah E. Bergen, PhD, Christina M. Hultman, PhD, Anna K. Kähler, PhD, and Patrick F. Sullivan, MD, FRANZCP); Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts (Sarah E. Bergen, PhD, Menachem Fromer, PhD, Aarno Palotie, MD, PhD, Tracey L. Petryshen, PhD, and Jordan W. Smoller, MD, ScD); Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City (Donald W. Black, MD); Division of Psychiatry, University of Edinburgh, Edinburgh, Scotland (Douglas H. R. Blackwood, PhD, FRCPsych); Department of Biomedicine, Aarhus University, Aarhus, Denmark (Anders D. Børglum, MD, PhD, Ditte Demontis, MSc, PhD, and Jakob Grove, MSc, PhD); Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark (Anders D. Børglum, MD, PhD, Ditte Demontis, MSc, PhD, Jakob Grove, MSc, PhD, Ole Mors, MD, PhD, and Preben B. Mortensen, MD, DMSc); Aarhus University Hospital, Risskov, Denmark (Anders D. Børglum, MD, PhD); The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (Anders D. Børglum, MD, PhD, Ditte Demontis, MSc, PhD, Jakob Grove, MSc, PhD, Ole Mors, MD, PhD, and Preben B. Mortensen, MD, DMSc); School of Nursing, Louisiana State University Health Sciences Center, New Orleans (Nancy G. Buccola, APRN, BC); Center for Brain Science, Harvard University, Cambridge, Massachusetts (Randy L. Buckner, PhD); Department of Psychiatry, Massachusetts General Hospital, Boston (Randy L. Buckner, PhD); Athinoula A. Martinos Center, Massachusetts General Hospital, Boston (Randy L. Buckner, PhD, and Joshua L. Roffman, MD, MMSc); Department of Psychiatry, University of California at San Francisco (William Byerley, MD); University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, the Netherlands (Wiepke Cahn, MD, PhD, René S. Kahn, MD, PhD, Roel A. Ophoff, PhD, and Eric Strengman, BSc); Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York (Guiqing Cai, MD, Kenneth L. Davis, MD, Joseph I. Friedman, MD, Vahram Haroutunian, PhD, Elena Parkhomenko, PhD, Abraham Reichenberg, PhD, and Jeremy M. Silverman, PhD); Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, New York (Guiqing Cai, MD); Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France (Dominique Campion, MD, PhD); Schizophrenia Research Institute, Sydney, Australia (Vaughan J. Carr, MD, FRANZCP, FRCPC, Stanley V. Catts, MD, FRANZCP, and Assen V. Jablensky, MD, DMSc, FRANZCP, FRCPsych); School of Psychiatry, University of New South Wales, Sydney, Australia (Vaughan J. Carr, MD, FRANZCP, FRCPC); MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, England (Noa Carrera, PhD, Nick Craddock, MD, PhD, Marian L. Hamshere, PhD, Peter A. Holmans, PhD, David Kavanagh, PhD, George Kirov, MD, PhD, Sophie E. Legge, BSc, Michael C. O’Donovan, MD, PhD, Michael J. Owen, MD, PhD, Andrew J. Pocklington, PhD, Alexander L. Richards, PhD, James T. R. Walters, MD, PhD, and Nigel M. Williams, PhD); Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, Australia (Stanley V. Catts, MD, FRANZCP); University of Aberdeen, Institute of Medical Sciences, Aberdeen, Scotland (David St Clair, MD, PhD); Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland (Paul Cormican, PhD, Aiden Corvin, MD, PhD, and Michael Gill, MRCPsych, MD); National Centre for Mental Health, Cardiff University, Cardiff, England (Nick Craddock, MD, PhD, Peter A. Holmans, PhD, Michael C. O’Donovan, MD, PhD, Michael J. Owen, MD, PhD, and Alexander L. Richards, PhD); Department of Genetics, The University of North Carolina at Chapel Hill (James J. Crowley, PhD, Patrick F. Sullivan, MD, FRANZCP, Jin P. Szatkiewicz, PhD, and Stephanie Williams, ScM); Department of Psychological Medicine, Queen Mary University of London, London, England (David Curtis, MD, PhD, MRCPsych); Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, England (David Curtis, MD, PhD, MRCPsych, Hugh Gurling, MPhil, MD, FRCPsych, and Jonathan Pimm, MB, BS, MD, MRCPsych); Sheba Medical Center, Tel Hashomer, Israel (Michael Davidson, MD); First Department of Psychiatry, University of Athens Medical School, Athens, Greece (Dimitris Dikeos, MD, and George N. Papadimitriou, MD); Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois (Jubao Duan, PhD, Pablo V. Gejman, MD, and Alan R. Sanders, MD); Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois (Jubao Duan, PhD, Pablo V. Gejman, MD, and Alan R. Sanders, MD); Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, England (Frank Dudbridge, PhD); Department of Psychiatry, University of Regensburg, Regensburg, Germany (Peter Eichhammer, MD, PhD); Estonian Genome Center, University of Tartu, Tartu, Estonia (Tõnu Esko, PhD, Andres Metspalu, MD, PhD, Lili Milani, PhD, and Mari Nelis, PhD); Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, Massachusetts (Tõnu Esko, PhD); Department of Genetics, Harvard Medical School, Boston, Massachusetts (Tõnu Esko, PhD, and Steven A. McCarroll, PhD); Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts (Tõnu Esko, PhD, and Eli A. Stahl, PhD); Mental Health Service Line, Washington VA Medical Center, Washington, DC (Ayman H. Fanous, MD); Department of Psychiatry, Georgetown University School of Medicine, Washington, DC (Ayman H. Fanous, MD); Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond (Ayman H. Fanous, MD); Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles (Ayman H. Fanous, MD); Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium (Jurgen Del Favero, PhD); King’s College London, London, England (Marta di Forti, MBBS, MRCPsych, PhD, Eugenia Kravariti, PhD, Robin M. Murray, FRS, Marco Picchioni, MBBS, MRCPsych, PhD, and John Powell, PhD); Department of Psychiatry, University of Colorado Denver, Aurora (Robert Freedman, MD); Department of Psychiatry, University of Halle, Halle, Germany (Marion Friedl, PhD, Ina Giegling, PhD, Annette M. Hartmann, PhD, Bettina Konte, MSc, and Dan Rujescu, MD, PhD); Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York (Menachem Fromer, PhD, Panos Roussos, MD, PhD, Pamela Sklar, MD, PhD, and Eli A. Stahl, PhD); Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston (Menachem Fromer, PhD); Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston (Menachem Fromer, PhD); Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, Illinois (Elliot S. Gershon, MD); Department of Psychiatry, University of Munich, Munich, Germany (Ina Giegling, PhD); Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France (Stephanie Godard, MS); Queensland Brain Institute, The University of Queensland, Brisbane, Australia (Jacob Gratten, PhD); Mclean Hospital, Harvard Medical School, Belmont, Massachusetts (Mei-Hua Hall, PhD); Illumina, La Jolla, California (Mark Hansen, PhD); Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Copenhagan, Denmark (Thomas Hansen, MSc, PhD, Line Olsen, MSc, PhD, Henrik B. Rasmussen, DVM, PhD, and Thomas Werge, MSc, PhD); The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (Thomas Hansen, MSc, PhD, Line Olsen, MSc, PhD, Henrik B. Rasmussen, DVM, PhD, and Thomas Werge, MSc, PhD); J. J. Peters VA Medical Center, Bronx, New York, New York (Vahram Haroutunian, PhD); Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York (Vahram Haroutunian, PhD, and Pamela Sklar, MD, PhD); Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark (David M. Hougaard, MD); School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth (Assen V. Jablensky, MD, DMSc, FRANZCP, FRCPsych); Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth (Assen V. Jablensky, MD, DMSc, FRANZCP, FRCPsych); The Perkins Institute for Medical Research, The University of Western Australia, Perth (Assen V. Jablensky, MD, DMSc, FRANZCP, FRCPsych); Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden (Erik G. Jönsson, MD, PhD, and Erik Söderman, PhD); Centre for Medical Research, The University of Western Australia, Perth (Luba Kalaydjieva, MD, PhD); The Perkins Institute for Medical Research, The University of Western Australia, Perth (Luba Kalaydjieva, MD, PhD); Department of Medical Genetics, Medical University, Sofia, Bulgaria (Sena Karachanak-Yankova, PhD); Department of Psychology, University of Colorado Boulder, Boulder (Matthew C. Keller, PhD); Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, Australia (Brian J. Kelly, PhD, FRANZCP); Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond (Kenneth S. Kendler, MD, and Brien P. Riley, PhD); Latvian Biomedical Research and Study Centre, Riga, Latvia (Janis Klovins, PhD, and Liene Nikitina-Zake, MD, PhD); Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles (James A. Knowles, MD, PhD, Carlos N. Pato, MD, PhD, and Michele T. Pato, MD); Faculty of Medicine, Vilnius University, Vilnius, Lithuania (Vaidutis Kucinskas, PhD, and Zita Ausrele Kucinskiene, MD, PhD); Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic (Hana Kuzelova-Ptackova, PhD); Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France (Claudine Laurent, MD, PhD); The Zucker Hillside Hospital, Glen Oaks, New York (Todd Lencz, PhD, and Anil K. Malhotra, MD); The Feinstein Institute for Medical Research, Manhasset, New York (Todd Lencz, PhD, and Anil K. Malhotra, MD); The Hofstra NS-LIJ School of Medicine, Hempstead, New York (Todd Lencz, PhD); Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland (Kung-Yee Liang, PhD); Department of Psychiatry, Columbia University, New York, New York (Jeffrey Lieberman, MD, and T. Scott Stroup, MD, MPH); Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland (Jan Lubinski, MD, PhD); Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland (Brion S. Maher, PhD); Department of Psychiatry, University of Bonn, Bonn, Germany (Wolfgang Maier, MD); The Hofstra NS-LIJ School of Medicine, Hempstead, New York (Anil K. Malhotra, MD); Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, Paris, France (Jacques Mallet, PhD); Research Unit, Sørlandet Hospital, Kristiansand, Norway (Morten Mattingsdal, MS); Department of Psychiatry, National University of Ireland Galway, Galway (Colm McDonald, MD, PhD); Academic Medical Centre University of Amsterdam, Department of Psychiatry, Amsterdam, the Netherlands (Carin J. Meijer, PhD); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (Ingrid Melle, MD, PhD); Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston (Raquelle I. Mesholam-Gately, PhD); Department of Psychiatry, Harvard Medical School, Boston, Massachusetts (Raquelle I. Mesholam-Gately, PhD, and Tracey L. Petryshen, PhD); First Psychiatric Clinic, Medical University, Sofia, Bulgaria (Vihra Milanova, MD, PhD); Aarhus University Hospital, Risskov, Denmark (Ole Mors, MD, PhD); National Centre for Register-Based Research, and Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark (Preben B. Mortensen, MD, DMSc); Queensland Brain Institute, The University of Queensland, Brisbane, Australia (Bryan J. Mowry, MB, BS, MD, FRANZCP); Queensland Centre for Mental Health Research, The University of Queensland, Brisbane, Australia (Bryan J. Mowry, MB, BS, MD, FRANZCP, and Deborah A. Nertney, BSc); Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland (Gerald Nestadt, MBBCh, MPH, and Ann E. Pulver, PhD); DETECT Early Intervention Service for Psychosis, Blackrock, Dublin, Ireland (Eadbhard O’Callaghan, MD, DSc, FRCPsych); Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, Ireland (F. Anthony O’Neill, MD, PhD); Lawrence Berkeley National Laboratory, University of California at Berkeley (Sang-Yun Oh, PhD); Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (Roel A. Ophoff, PhD); Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles (Roel A. Ophoff, PhD); Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki (Aarno Palotie, MD, PhD); Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston (Aarno Palotie, MD, PhD, and Jordan W. Smoller, MD, ScD); Department of Psychiatry, The University of North Carolina at Chapel Hill (Diana O. Perkins, MD, MPH, and Patrick F. Sullivan, MD, FRANZCP); Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston (Tracey L. Petryshen, PhD); Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond (Mark A. Reimers, PhD, and Aaron R. Wolen, PhD); Department of Psychiatry, Massachusetts General Hospital, Boston (Joshua L. Roffman, MD, MMSc); Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York (Panos Roussos, MD, PhD, and Pamela Sklar, MD, PhD); Department of Psychiatry, University of Munich, Munich, Germany (Dan Rujescu, MD, PhD); PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts (Christian R. Schubert, PhD, and Jens R. Wendland, MD); Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany (Sibylle G. Schwab, PhD); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland (Jianxin Shi, PhD); Research and Development, Bronx Veterans Affairs Medical Center, New York, New York (Jeremy M. Silverman, PhD); Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia (Petr Slominsky, PhD); Wellcome Trust Centre for Human Genetics, Oxford, England (Chris C. A. Spencer, PhD); Department of Clinical Neurology, Medical University of Vienna, Wien, Austria (Elisabeth Stogmann, MD, and Fritz Zimprich, MD, PhD); Lieber Institute for Brain Development, Baltimore, Maryland (Richard E. Straub, PhD); Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands (Eric Strengman, BSc); Department of Psychiatry, Washington University in St Louis, Missouri (Dragan M. Svrakic, MD, PhD); Berkshire Healthcare NHS Foundation Trust, Bracknell, England (Srinivas Thirumalai, MB, BS, MD, MRCPsycH); Department of Psychology, The University of Hong Kong, Hong Kong, China (Timothea Toulopoulou, PhD); Health Research Board, Dublin, Ireland (Dermot Walsh, MD); Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond (Bradley T. Webb, PhD); Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark (Thomas Werge, MSc, PhD); School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth (Dieter B. Wildenauer, PhD); and Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, Massachusetts (Hualin Simon Xi, PhD).

Additional Contributions: The acknowledgments for the Schizophrenia Working Group of the Psychiatric Genomics Consortium data are listed in reference 15 and in eAppendix 3 in the Supplement. The SNP&SEQ Technology Platform at Uppsala University Sweden is acknowledged for performing genotyping and for excellent technical assistance. We acknowledge Estonian Genome Center Biobank, University of Tartu, technical personnel, especially Viljo Soo and Steven Smith.

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