Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors

Andreassen, Ole A., Djurovic, Srdjan, Thompson, Wesley K., Schork, Andrew J., Kendler, Kenneth S., O'Donovan, Michael C., Rujescu, Dan, Werge, Thomas, van de Bunt, Martijn, Morris, Andrew P., McCarthy, Mark I., Roddey, J. Cooper, McEvoy, Linda K., Desikan, Rahul S., Dale, Anders M., International Consortium for Blood Pressure GWAS and Mowry, Bryan (2013) Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors. American Journal of Human Genetics, 92 2: 197-209. doi:10.1016/j.ajhg.2013.01.001


Author Andreassen, Ole A.
Djurovic, Srdjan
Thompson, Wesley K.
Schork, Andrew J.
Kendler, Kenneth S.
O'Donovan, Michael C.
Rujescu, Dan
Werge, Thomas
van de Bunt, Martijn
Morris, Andrew P.
McCarthy, Mark I.
Roddey, J. Cooper
McEvoy, Linda K.
Desikan, Rahul S.
Dale, Anders M.
International Consortium for Blood Pressure GWAS
Mowry, Bryan
Title Improved detection of common variants associated with schizophrenia by leveraging pleiotropy with cardiovascular-disease risk factors
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-02-07
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.01.001
Open Access Status Not yet assessed
Volume 92
Issue 2
Start page 197
End page 209
Total pages 13
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
 
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