Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.

Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Keywords: Cholesterol; GWAS; Genetics; Genome-wide association study; Lipids.

Fig. 1

Schematic of multi-method candidate gene mapping of indexed variants associated with blood lipid levels. We defined indexed variants within the GLGC GWAS summary statistics and performed two similarity-based methods and four locus-based methods to prioritize genes for each of the indexed variants

Fig. 2

PheWAS meta-analysis results for multi-ancestry LDL-C PGS in the UK Biobank and MVP. The blue horizontal line denotes phenome-wide significance (p-value ≤ 6.5 × 10⁻⁵, to account for multiple testing of 773 phenotypes) and the red line is genome-wide significance (p-value ≤ 5 × 10⁻⁸). Phenotypes have been pruned, so that the most significant one per correlated phenotype group (correlation coefficient > 0.2) is retained. Pairwise correlations were estimated with chi-square test and Cramer’s V for the dichotomous phenotypes and Pearson’s correlation for the continuous phenotypes. AAA: abdominal aortic aneurysm, AD: Alzheimer’s disease, AST: aspartate aminotransferase, Atherosclerosis*: atherosclerosis of native arteries of the extremities with intermittent claudication, Hb_con: hemoglobin concentration, IBD: irritable bowel disease, MCH: mean corpuscular hemoglobin, MCV: mean corpuscular volume, PVD: peripheral vascular disease

Fig. 3

Sex specificity at the UGT2B17 Locus. A The association signal for LDL-C (top panel) colocalizes with the UGT2B17 eQTL signal in the liver (bottom panel). B The effect sizes of this variant on LDL-C and UGT2B17 expression are both significantly higher for males (red) compared to females (blue)