title: Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors.
abstract: Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.
authors: K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo 0407, Norway. o.a.andreassen@medisin.uio.no
authors: Ole A
authors: OA
authors: Andreassen
authors: Srdjan
authors: S
authors: Djurovic
authors: Wesley K
authors: WK
authors: Thompson
authors: Andrew J
authors: AJ
authors: Schork
authors: Kenneth S
authors: KS
authors: Kendler
authors: Michael C
authors: MC
authors: O'Donovan
authors: Dan
authors: D
authors: Rujescu
authors: Thomas
authors: T
authors: Werge
authors: Martijn
authors: M
authors: van de Bunt
authors: Andrew P
authors: AP
authors: Morris
authors: Mark I
authors: MI
authors: McCarthy
authors: J Cooper
authors: JC
authors: Roddey
authors: Linda K
authors: LK
authors: McEvoy
authors: Rahul S
authors: RS
authors: Desikan
authors: Anders M
authors: AM
authors: Dale
mesh_terms: D002318:Cardiovascular Diseases / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
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