PT - JOURNAL ARTICLE AU - Guillaume Pare AU - Shihong Mao AU - Wei Q. Deng TI - Regional polygenic covariance reveals heterogeneity in the shared heritability between complex traits AID - 10.1101/143644 DP - 2017 Jan 01 TA - bioRxiv PG - 143644 4099 - http://biorxiv.org/content/early/2017/05/29/143644.short 4100 - http://biorxiv.org/content/early/2017/05/29/143644.full AB - Complex traits can share a substantial proportion of their polygenic heritability. However, genome-wide polygenic correlations between a pair of traits can mask heterogeneity in their shared polygenic effects across loci. We propose a novel method (WML-RCP) to evaluate polygenic covariance between two complex traits in small genomic regions using summary association statistics. Our method makes no assumption about the causality of one trait on the other, but rather tests for evidence that the polygenic effect at a given region affects two traits concurrently. We show through simulations that our method is well calibrated and more powerful than other co-localisation methods under a polygenic model. As small genomic regions are more likely to harbour specific genetic effects, our method is ideal to identify heterogeneity in shared polygenic covariance across regions. We illustrate the usefulness of our method by addressing three questions related to cardio-metabolic traits. First, we explore how regional polygenic covariance can inform on the strong epidemiological association between HDL cholesterol and coronary artery disease (CAD), suggesting a key role for triglycerides metabolism. Second, we identify a ~4Mb region including PPP1R3B on chromosome 8p23.1 with paradoxical polygenic covariance between triglycerides and BMI, as well as evidence of polygenic inheritance and pairwise covariance with multiple other metabolic traits. Finally, we investigate the potential role of PPARĪ³ activators in the prevention of CAD. Our results provide a compelling argument that shared heritability between complex traits is highly heterogeneous across loci.