Cross-disorder genomewide analysis of schizophrenia, bipolar disorder, and depression
Open accessAbstract
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 significant 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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Subsequent studies have linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder, major depression, and intellectual disability.
“Subsequent studies have further linked NPAS3 to multiple human psychiatric and neurodevelopmental disorders, including bipolar disorder (Pickard et al. 2009; Huang et al. 2010; Nurnberger et al. 2014), schizophrenia (Pickard et al. 2005, 2006, 2009; Huang et al. 2010; Macintyre et al. 2010; Yu et al. 2014)”
From The Human Accelerated Region HAR202 Controls <i>NPAS3</i> Expression in the Developing Forebrain Displaying Differential Enhancer Activity Between Modern and Archaic Human Sequences (2024) · cites this paper as Huang et al. 2010
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References 58 · Cited by 213
Research works printed but not linked: 2
- [41]Endicott J Nee J Andreasen N Clayton P Keller M Coryell W Bipolar II Combine or keep separate? J Affect Disord 1985 8 1 17 28 3156908
- [58]Purcell S Perlis RH Sullivan PF Sklar P Smoller JW Modifiers and subtype-specific genes in whole-genome association studies of complex disease submitted PMC7077092 21849790
- Authors
- Huang, J., Perlis, R. H., Lee, P. H., Rush, A. J., Fava, M., Sachs, G. S., Lieberman, J., Hamilton, S. P., Sullivan, P., Sklar, P., Purcell, S., & Smoller, J. W.
- Affiliations
- Broad Institute (US)
- 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,...
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2010-10
- Volume
- 167
- Issue
- 10
- Pages
- 1254-1263
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC3880556
- OpenAlex
- W2110361971
- Cited by
- 213
- References
- 58
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 11 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 8 · 2017: 11 · 2016: 17 · 2015: 12 · 2014: 12 · 2013: 30 · 2012: 33
- FWCI
- 20.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (n01mh80001-12-0-0, n01mh90003-26-0-0, n01mh90001-21-0-0)
- National Institute of Mental Health (MH59566, N01 MH90001, N01‐MH‐90003, N01-MH80001, MH-60870, R01MH079799, R01MH072802, MH-059565, N01 MH090003, MH-079799, MH067257, MH-061675, MH-59586, R01MH059566, R01MH059571, MH-059571, R01MH060879, R01MH059565, N01 MH090001, R01MH060870, U01 MH-060879, R01MH061675, R01MH059586, N01 MH080001, R01MH059588, R01MH067257, MH-59587, R01MH079777, MH-059588, R01MH059587)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- schizophrenia, bipolar disorder, major depressive disorder, pleiotropy, adrenomedullin, NPAS3, bipolar II disorder, genetic specificity, mood disorders, psychosis, chromosome 11p15
- MeSH terms
- Adult, Bipolar Disorder, Carrier Proteins, Chromosome Mapping, Chromosomes, Human, Pair 11, Major Depressive Disorder, Female, Gene Frequency, Genotype, Humans, Genetic Linkage, Male, Nerve Tissue Proteins, Phenotype, Schizophrenia, Transcription Factors, Randomized Controlled Trials as Topic, Cytokines, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Basic Helix-Loop-Helix Proteins, Adrenomedullin, Genome-Wide Association Study
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