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

Authors

Ole A. Andreassen, University of Oslo
Wesley K. Thompson, University of California San Diego
Andrew J. Schork, University of California San Diego
Stephan Ripke, Massachusetts General Hospital
Morten Mattingsdal, University of Oslo
John R. Kelsoe, University of California San Diego
Kenneth S. Kendler, Virginia Commonwealth UniversityFollow
Michael C. O'Donovan, Cardiff University
Dan Rujescu, University of Halle-Wittenberg
Thomas Werge, University of Copenhagen
Pamela Sklar, Mount Sinai School of Medicine
J. Cooper Roddey, University of California San Diego
Chi-Hua Chen, University of California San Diego
Linda McEvoy, University of California San Diego
Rahul S. Desikan, University of California San Diego
Srdjan Djurovic, University of Oslo
Anders M. Dale, University of California San Diego

Document Type

Article

Original Publication Date

2013

Journal/Book/Conference Title

PLOS Genet

Volume

9

DOI of Original Publication

10.1371/journal.pgen.1003455

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pgen.1003455

Date of Submission

November 2014

Abstract

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 versawith 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.

Rights

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.

Is Part Of

VCU Psychiatry Publications