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


  • Financial disclosures: Dr. Barnett is an employee of Cambridge Cognition, a company that makes cognitive testing software. Dr. Sklar has served as a consultant for Pfizer, Inc., and is on the Board of Directors of Catalytic. Dr. Sullivan has received unrestricted research support from Eli Lilly and Expression Analysis (SAB). Dr. Perlis has received consulting fees or served on scientific advisory boards for Genomind, Healthrageous, Pamlab, Proteus Biomedical, and RIDVentures. He has received research support from Proteus Biomedical. He receives royalties/patent fees from Concordant Rater Systems (now UBC/Medco). Drs. McGrath, Cornelis, Lee, Robinson, Huang, Smoller and Ms. Gerber report no biomedical financial interests or potential conflicts of interest.


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. © 2013 Wiley Periodicals, Inc.