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

Genetic variants within nearly 1,000 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. 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 2,286 lipid associations by combining six gene prediction methods and assigning a confidence score. We assign, most confidently, 118 candidate causal genes and identify potential drug targets including bona-fide (PCSK9) and putative (PNLIP and ARF6) genes. 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. Taken together, our findings provide insights into the mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.