Cohort-wide deep whole genome sequencing and the allelic architecture of complex traits

Abstract

The role of rare variants in complex traits remains uncharted. Here, we conduct deep whole genome sequencing of 1,457 individuals from an isolated population, and test for rare variant burdens across six cardiometabolic traits. We identify a role for rare regulatory variation, which has hitherto been missed. We find evidence of rare variant burdens overlapping with, and mostly independent of established common variant signals (ADIPOQ and adiponectin, P=4.2x10^-8; APOC3 and triglyceride levels, P=1.58x10^-26; GGT1 and gamma-glutamyltransferase, P=2.3x10^-6; UGT1A9 and bilirubin, P=1.9x10^-8), and identify replicating evidence for a burden associated with triglyceride levels in FAM189A (P=2.26x10^-8), indicating a role for this gene in lipid metabolism.