Andreassen, Ole A3; Thompson, Wesley K3; Schork, Andrew J3; Ripke, Stephan3; Mattingsdal, Morten3; Kelsoe, John R3; Kendler, Kenneth S3; O'Donovan, Michael C3; Rujescu, Dan3; Werge, Thomas4; Sklar, Pamela3; Roddey, J Cooper3; Chen, Chi-Hua3; McEvoy, Linda3; Desikan, Rahul S3; Djurovic, Srdjan3; Dale, Anders M3
1 Graduate School of Health and Medical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 Section of Neurology, Psychiatry and Sensory Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section of Neurology, Psychiatry and Sensory Sciences, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Københavns Universitet
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.