GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal

Abstract

Perturbation of lipid homoeostasis 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 lipid traits. Most of these loci were already known in Europeans, however, we found 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 (β_SD(SE) = -0.22 (0.03), p = 6.5 × 10^-12) and total cholesterol (-0.17 (0.03), p = 1.1 × 10^-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 European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance.

Fig. 1. Genome-wide association studies of six lipid traits.

A Manhattan plot for each trait. Association signals have been truncated at −log(p) = 15 indicated by pink dots. The dashed line indicates genome-wide significance (p < 5 × 10⁻⁸). B Effect size estimates (beta) and significance level (p) for all combinations of the six lipid traits and the lead variants from the 11 genome-wide significant loci identified in the GWAS. ApoA1 apolipoprotein A1, apoB apolipoprotein B. HDL-C HDL-cholesterol, LDL-C, LDL-cholesterol, TC total cholesterol, TG, triglycerides.

Fig. 2. Association signal near PCSK9.

A Locus zoom of the LDL-cholesterol association signal at chromosome 1. The colour of the dots indicates the linkage equilibrium in the Inuit ancestry only with the lead variant rs4927191 (dark red dot). B The LDL-cholesterol association signal conditioned on the PCSK9 loss-of-function variant (rs11591147). C Schematic representation of the PCSK9 locus. D eQTL signals for PCSK9 across tissues from GTEx with p < 2.0 × 10⁻⁴. The top 6 variants from the LDL-cholesterol-association signal near PCSK9 are highlighted with colours Adipose-Sub, subcutaneous adipose tissue; Adipose Vis, visceral adipose tissue; Cerebellar Hemi, Cerebellar Hemisphere; Oesophagus - Mus, Oesophagus - Muscularis; Skin 1, not sun-exposed skin (Suprapubic). Data were obtained from the GTEx Portal [34].

Fig. 3. Association analyses of the potential causal variant near PCSK9.

Association results for rs12117661 and Circulating lipid levels in (A) Greenlanders and (B) Europeans from the UK Biobank, as well as cardiovascular disease outcomes in (C) Greenlanders and (D) Europeans from the UK Biobank. Hazard ratios and 95% confidence intervals were estimated with a Cox regression model adjusted for age, sex, and PC1-10.

Fig. 4. Partial variance explained by the genetic risk scores (GRS), age, and BMI.

Explained variance was estimated for each lipid trait as the partial r² in a model including all variables and adjusted for age, BMI, and principal components 1–10.