Title Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate Permalink

Several lines of evidence suggest that genome-wide association studies (GWAS) have the potential to explain more of the ‘‘missing heritability’’ of common complex phenotypes. However, reliable methods to identify a larger proportion of single nucleotide polymorphisms (SNPs) that impact disease risk are currently lacking. Here, we use a genetic pleiotropy-informed conditional false discovery rate (FDR) method on GWAS summary statistics data to identify new loci associated with schizophrenia (SCZ) and bipolar disorders (BD), two highly heritable disorders with significant missing heritability. Epidemiological and clinical evidence suggest similar disease characteristics and overlapping genes between SCZ and BD. Here, we computed conditional Q–Q curves of data from the Psychiatric Genome Consortium (SCZ; n = 9,379 cases and n = 7,736 controls; BD: n = 6,990 cases and n = 4,820 controls) to show enrichment of SNPs associated with SCZ as a function of association with BD and vice versa with a corresponding reduction in FDR. Applying the conditional FDR method, we identified 58 loci associated with SCZ and 35 loci associated with BD below the conditional FDR level of 0.05. Of these, 14 loci were associated with both SCZ and BD (conjunction FDR). Together, these findings show the feasibility of genetic pleiotropy-informed methods to improve gene discovery in SCZ and BD and indicate overlapping genetic mechanisms between these two disorders. Citation: Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M, et al. (2013) Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate. PLoS Genet 9(4): e1003455. doi:10.1371/journal.pgen.1003455 Editor: Peter M. Visscher, The University of Queensland, Australia Received August 21, 2012; Accepted March 4, 2013; Published April 25, 2013 Copyright: 2013 Andreassen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: OAA was supported by grants from the Research Council of Norway (www.forskningsradet.no), the South-East Norway Health Authority (www.helsesorost.no), the Kristian Gerhard Jebsen Foundation (http://www.stiftkgj.no), and the US–Norway Fulbright Foundation. RSD was supported by a grant from the National Institutes of Health (NIH; www.nih.gov T32 EB005970). AMD was supported by NIH grants R01AG031224, R01EB000790, and RC2DA29475. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: amdale@ucsd.edu (AMD); o.a.andreassen@medisin.uio.no (OAA)