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Published Online: 1 October 2010

Cross-Disorder Genomewide Analysis of Schizophrenia, Bipolar Disorder, and Depression

Jie Huang, M.D., M.S., M.P.H., Roy H. Perlis, M.D., M.S., Phil H. Lee, Ph.D., A. John Rush, M.D., Maurizio Fava, M.D., Gary S. Sachs, M.D., Jeffrey Lieberman, M.D., Steven P. Hamilton, M.D., Ph.D., Patrick Sullivan, M.D., Pamela Sklar, M.D., Ph.D., Shaun Purcell, Ph.D., and Jordan W. Smoller, M.D., Sc.D.Authors Info & Affiliations
Publication: American Journal of Psychiatry
Volume 167, Number 10
https://doi.org/10.1176/appi.ajp.2010.09091335
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Abstract

Objective:

Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders.

Method:

The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, geno-typed: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders.

Results:

The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder.

Conclusions:

This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11p15 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide signifi-cant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
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American Journal of Psychiatry
Volume 167 • Number 10 • October 2010
Pages: 1254 - 1263
PubMed: 20713499

History

Received: 21 September 2009
Revision received: 10 March 2010
Accepted: 8 April 2010
Published online: 1 October 2010
Published in print: October 2010

Authors

Affiliations

Jie Huang, M.D., M.S., M.P.H.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Roy H. Perlis, M.D., M.S.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Phil H. Lee, Ph.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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A. John Rush, M.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Maurizio Fava, M.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Gary S. Sachs, M.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Jeffrey Lieberman, M.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Steven P. Hamilton, M.D., Ph.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Patrick Sullivan, M.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Pamela Sklar, M.D., Ph.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Shaun Purcell, Ph.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Jordan W. Smoller, M.D., Sc.D.
From the Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry, Massachusetts General Hospital, Boston; the Stanley Center for Psychiatric Research, Broad Institute, Cambridge, Mass.; the Duke-National University of Singapore Graduate Medical School, Singapore; the Department of Psychiatry, College of Physicians and Surgeons, Columbia University and New York State Psychiatric Institute, New York; the Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco; and the Departments of Genetics, Psychiatry, and Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, N.C.
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Notes

Address correspondence and reprint requests to Dr. Smoller, Center for Human Genetic Research, Simches Research Building, 185 Cambridge St., Boston, MA 02114; [email protected] (e-mail).

Funding Information

Supported by the National Institutes of Health grant MH-079799 (Dr. Smoller).

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