Genome-wide association study of lipids in Greenlandic Inuit shows independent PCSK9 association and reveals a unique genetic architecture

Abstract Perturbation of lipid homeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with at least one of the lipid traits, and a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (βSD(SE)=-0.22 (0.03), p=6.5x10-12) and total cholesterol (-0.17 (0.03), p=1.1x10-8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in GTEx, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS hits explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is markedly different from Europeans, with fewer variants explaining the variance.