Genetic predictors of risk and resilience in psychiatric disorders: a cross-disorder genome-wide association study of functional impairment in major depressive disorder, bipolar disorder, and schizophrenia
Open accessAbstract
Functional impairment is one of the most enduring, intractable consequences of psychiatric disorders and is both familial and heritable. Previous studies have suggested that variation in functional impairment can be independent of symptom severity. Here we report the first genome-wide association study (GWAS) of functional impairment in the context of major mental illness. Participants of European-American descent (N = 2,246) were included from three large treatment studies of bipolar disorder (STEP-BD) (N = 765), major depressive disorder (STAR*D) (N = 1091), and schizophrenia (CATIE) (N = 390). At study entry, participants completed the SF-12, a widely used measure of health-related quality of life. We performed a GWAS and pathway analysis of the mental and physical components of health-related quality of life across diagnosis (∼1.6 million single nucleotide polymorphisms), adjusting for psychiatric symptom severity. Psychiatric symptom severity was a significant predictor of functional impairment, but it accounted for less than one-third of the variance across disorders. After controlling for diagnostic category and symptom severity, the strongest evidence of genetic association was between variants in ADAMTS16 and physical functioning (P = 5.87 × 10(-8) ). Pathway analysis did not indicate significant enrichment after correction for gene clustering and multiple testing. This study illustrates a phenotypic framework for examining genetic contributions to functional impairment across psychiatric disorders.
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Findings from genetic association and GWAS analyses suggest that several metzincin protease genes, including ADAMTSL3, ADAMTS12, ADAMTS-16, ADAM22, and MMP16, may confer vulnerability to schizophrenia.
“First, converging results from several recent genetic association and genome-wide association studies indicate that genes encoding for a number of metzincin metalloproteases may represent vulnerability factors for SZ.”
From Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia (2015) · cites this paper as McGrath et al., 2013
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- Authors
- McGrath, L. M., Cornelis, M. C., Lee, P. H., Robinson, E. B., Duncan, L. E., Barnett, J. H., Huang, J., Gerber, G., Sklar, P., Sullivan, P., Perlis, R. H., & Smoller, J. W.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- Icahn School of Medicine at Mount Sinai (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- McGrath, Lauren M.
- ORCID
- Venue
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2013-09-13
- Volume
- 162
- Issue
- 8
- Pages
- 779-788
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- PMC
- PMC4019336
- OpenAlex
- W2087568826
- Cited by
- 48
- References
- 66
- Citations by year
- 2026: 4 · 2025: 3 · 2023: 2 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 5
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Eli Lilly and Company
- National Alliance for Research on Schizophrenia and Depression
- National Institute of Mental Health (R01MH079799, T32MH16259, K24MH094614, T32MH016259)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Keywords
- functional disability, health-related quality of life, major depressive disorder, bipolar disorder, schizophrenia, mental illness, genetic risk, resilience, ADAMTS16, physical function, symptom severity
- MeSH terms
- ADAMTS Proteins, Bipolar Disorder, Major Depressive Disorder, Humans, Phenotype, Risk Factors, Schizophrenia, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, ADAM Proteins, Genome-Wide Association Study, Resilience, Psychological, Genetic Loci
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