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New Research
Published Online: 1 December 2012
Genome-Wide Association Study of Clinical Dimensions of Schizophrenia: Polygenic Effect on Disorganized Symptoms
Ayman H. Fanous, M.D., Baiyu Zhou, Ph.D., Steven H. Aggen, Ph.D., Sarah E. Bergen, Ph.D., Richard L. Amdur, Ph.D., Jubao Duan, Ph.D., Alan R. Sanders, M.D., … Show All … , Jianxin Shi, Ph.D., Bryan J. Mowry, M.D., F.R.A.N.Z.C.P., Ann Olincy, M.D., Farooq Amin, M.D., C. Robert Cloninger, M.D., Jeremy M. Silverman, Ph.D., Nancy G. Buccola, M.S.N., A.P.R.N., William F. Byerley, M.D., Donald W. Black, M.D., Robert Freedman, M.D., Frank Dudbridge, Ph.D., Peter A. Holmans, Ph.D., Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium, Stephan Ripke, M.D., Pablo V. Gejman, M.D., Kenneth S. Kendler, M.D., and Douglas F. Levinson, M.D. Show FewerAuthors Info & Affiliations
Publication: American Journal of Psychiatry
Abstract
Objective
Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.
Method
Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, and mood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor.
Results
No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples.
Conclusions
The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia).
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Information & Authors
Information
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History
Received: 14 February 2012
Revision received: 23 May 2012
Accepted: 20 June 2012
Published online: 1 December 2012
Published in print: December 2012
Authors
Details
Ayman H. Fanous, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Baiyu Zhou, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Steven H. Aggen, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Sarah E. Bergen, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Richard L. Amdur, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Jubao Duan, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Alan R. Sanders, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Jianxin Shi, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Bryan J. Mowry, M.D., F.R.A.N.Z.C.P.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Ann Olincy, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Farooq Amin, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
C. Robert Cloninger, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Jeremy M. Silverman, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Nancy G. Buccola, M.S.N., A.P.R.N.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
William F. Byerley, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Donald W. Black, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Robert Freedman, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Frank Dudbridge, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Peter A. Holmans, Ph.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Stephan Ripke, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Pablo V. Gejman, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Kenneth S. Kendler, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Douglas F. Levinson, M.D.
From the Mental Health Service Line, Washington, D.C.; the Veterans Affairs Medical Center, Washington, D.C.; Department of Psychiatry, Georgetown University School of Medicine, Washington, D.C.; Departments of Psychiatry and Human Genetics, Virginia Commonwealth University, Richmond, Va.; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics Research, Massachusetts General Hospital, Boston; the Center for Psychiatric Genetics, NorthShore University HealthSystem Research Institute, Evanston, Ill.; Queensland Brain Institute, University of Queensland, Brisbane and Queensland Centre for Mental Health Research, Brisbane, Australia; Department of Psychiatry, University of Colorado Denver, Aurora, Colo.; Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, and Emory University, Atlanta; Department of Psychiatry, Washington University, St. Louis, Mo.; Department of Psychiatry, Mount Sinai School of Medicine, N.Y.; School of Nursing, Louisiana State University Health Sciences Center, New Orleans; Department of Psychiatry, University of California at San Francisco, San Francisco; the Mental Health Clinical Research Center, and Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City; the Medical Research Council-Biostatistics Unit, Institute of Public Health, Cambridge, United Kingdom; the MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Heath Park, Cardiff, United Kingdom; and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, and Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Mass.
Funding Information
Dr. Black has received research support from AstraZeneca. All other authors report no financial relationships with commercial interests.Drs. Fanous and Zhou contributed equally to this study.Members of the Genome-Wide Association Study Consortium are listed in the data supplement accompanying the online edition of this article.Data collection, genotyping, and analysis were supported by NIH R01 grants (MH-67257 to Dr. Buccola, MH-59588 to Dr. Mowry, MH-59571 to Dr. Gejman, MH-59565 to Dr. Freedman, MH-59587 to Dr. Amin, MH-60870 to Dr. Byerley, MH-59566 to Dr. Black, MH-59586 to Dr. Silverman, MH-61675 to Dr. Levinson, MH-60879 to Dr. Cloninger, and MH-81800 to Dr. Gejman), NIH U01 grants (MH-46276 to Dr. Cloninger, MH-46289 to Dr. Charles Kaufmann, MH-46318 to Dr. Ming T. Tsuang, MH-79469 to Dr. Gejman, and MH-79470 to Dr. Levinson), VA grant 1I01CX000278 (to Dr. Fanous), NARSAD Young Investigator Awards (to Drs. Duan and Saunders), the Genetic Association Information Network (GAIN), and the Paul Michael Donovan Charitable Foundation. Genotyping was carried out by the Broad Institute Center for Genotyping and Analysis at MIT and Harvard (by S. Gabriel and D.B. Mirel), with support from grant U54 RR020278 from the National Center for Research Resources. Genotyping of half of the European ancestry sample and almost all the African American sample was carried out with support from GAIN.
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