A novel random effect model for GWAS meta-analysis and its application to trans-ethnic meta-analysis

Meta-analysis of trans-ethnic genome-wide association studies (GWAS) has proven to be a practical and profitable approach for identifying loci that contribute to the risk of complex diseases. However, the expected genetic effect heterogeneity cannot easily be accommodated through existing fixed-effects and random-effects methods. In response, we propose a novel random effect model for trans-ethnic meta-analysis with flexible modeling of the expected genetic effect heterogeneity across diverse populations. Specifically, we adopt a modified random effect model from the kernel regression framework, in which genetic effect coefficients are random variables whose correlation structure reflects the genetic distances across ancestry groups. In addition, we use the adaptive variance component test to achieve robust power regardless of the degree of genetic effect heterogeneity. Simulation studies show that our proposed method has well-calibrated type I error rates at very stringent significance levels and can improve power over the traditional meta-analysis methods. We reanalyzed the published type 2 diabetes GWAS meta-analysis (Consortium et al., 2014) and successfully identified one additional SNP that clearly exhibits genetic effect heterogeneity across different ancestry groups. Furthermore, our proposed method provides scalable computing time for genome-wide datasets, in which an analysis of one million SNPs would require less than 3 hours.