title: 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.
abstract: 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.
authors.affiliation: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: McGrath
authors.forename: Marilyn C
authors.initials: MC
authors.lastname: Cornelis
authors.forename: Phil H
authors.initials: PH
authors.lastname: Lee
authors.forename: Elise B
authors.initials: EB
authors.lastname: Robinson
authors.forename: Laramie E
authors.initials: LE
authors.lastname: Duncan
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barnett
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Gloria
authors.initials: G
authors.lastname: Gerber
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.forename: Patrick
authors.initials: P
authors.lastname: Sullivan
authors.forename: Roy H
authors.initials: RH
authors.lastname: Perlis
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
mesh_terms: D051722:ADAM Proteins / Q000235:genetics; D000071096:ADAMTS Proteins; D001714:Bipolar Disorder / Q000235:genetics* / Q000503:physiopathology; D003865:Major Depressive Disorder / Q000235:genetics* / Q000503:physiopathology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055500:Resilience, Psychological; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology
chemical_list: D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C510098:ADAMTS16 protein, human
keywords: ADAMTS16; SF-12; disability; genetics; health-related quality of life
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