A powerful method for pleiotropic analysis under composite null hypothesis identifies novel shared loci between Type 2 Diabetes and Prostate Cancer

There is increasing evidence that pleiotropy, the association of multiple traits with the same genetic variants/loci, is a very common phenomenon. Cross-phenotype association tests are often used to jointly analyze multiple traits from a genome-wide association study (GWAS). The underlying methods, however, are often designed to test the global null hypothesis that there is no association of a genetic variant with any of the traits, the rejection of which does not implicate pleiotropy. In this article, we propose a new statistical approach, PLACO, for specifically detecting pleiotropic loci between two traits by considering an underlying composite null hypothesis that a variant is associated with none or only one of the traits. We propose testing the null hypothesis based on the product of the Z-statistics of the genetic variants across two studies and derive a null distribution of the test statistic in the form of a mixture distribution that allows for fractions of variants to be associated with none or only one of the traits. We borrow approaches from the statistical literature on mediation analysis that allow asymptotic approximation of the null distribution avoiding estimation of nuisance parameters related to mixture proportions and variance components. Simulation studies demonstrate that the proposed method can maintain type I error and can achieve major power gain over alternative simpler methods that are typically used for testing pleiotropy. PLACO allows correlation in summary statistics between studies that may arise due to sharing of controls between disease traits. Application of PLACO to publicly available summary data from two large case-control GWAS of Type 2 Diabetes and of Prostate Cancer implicated a number of novel shared genetic regions: 3q23 (ZBTB38), 6q25.3 (RGS17), 9p22.1 (HAUS6), 9p13.3 (UBAP2), 11p11.2 (RAPSN), 14q12 (AKAP6), 15q15 (KNL1) and 18q23 (ZNF236).Author summary: We propose a new approach PLACO that uses aggregate-level genotype-phenotype association statistics—commonly referred to as GWAS summary statistics—to identify genetic variants that influence risk of two traits or diseases. It allows correlation in summary statistics between studies that may arise due to sharing of controls between disease traits. We demonstrate that PLACO can achieve major power gain over alternative methods that are typically used. We applied PLACO to Type 2 Diabetes and Prostate Cancer summary data from two large case-control studies. Many previous studies have reported an inverse association of these two chronic diseases suggesting shared risk factors; however, shared genetic mechanisms underlying this association is poorly understood. PLACO identified a number of novel shared genetic regions that are not detected by individual trait analysis. Many of the loci implicated by PLACO increase risk for one disease while decreasing risk for the other. PLACO can similarly be used on other traits to shed light on shared genetic risk factors.