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

Abstract

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.

Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

“…Sex‐combined analyses are underpowered to detect significant associations if the effects are in opposite directions. Although sex heterogeneity in effect of a few lipid loci, such as LPL , APOE , and KLF , on traditional lipids has been reported, 51 , 52 there has been no effort to systematically evaluate differential effects of genetic variants on plasma lipidome in men and women. To our knowledge, our study presents the first comprehensive investigation of sexual heterogeneity in genetic influences on plasma lipidome.…”

Lipidome- and genome-wide study to understand sex differences in circulatory lipids

“…Sex-combined analyses are under-powered to detect significant associations if the effects are in opposite directions. Though sex-heterogeneity in effect of a few lipid loci such as LPL, APOE , and KLF on traditional lipids has been reported [37, 38], there has been no effort to systematically evaluate differential effects of genetic variants on plasma lipidome in men and women. To our knowledge, our study presents the first comprehensive investigation of sex-dimorphism in genetic influences on plasma lipidome.…”

The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk

“…total cholesterol and HDL, etc) and blood cell counts. More importantly, we performed comprehensive univariable and multivariable MR analyses, using SNPs identified from the latest GWAS for CHD 44,62,63,64 , LDL 65,66 and mtDNA CN 61 to explore the causal relationships between mtDNA CN, LDL and CHD. We applied the MR-PRESSO and MR-Egger tests as well as several sensitivity analyses to minimize the bias and to test validity of MR analyses.…”

“…71 Robust genetic variants have been identified in large GWAS with mtDNA CN (n = 465,809), CHD (n = 361,194) and LDL (n=1,166,583). 61,62,72,73,74 To minimize bias in MR analyses, we removed known pleiotropic SNPs (e.g., APOE SNPs) that are associated with both mtDNA CN and CVD traits. We performed MR IVW as well as sensitivity analyses including MR-Egger, Median and Mode methods to provide evidence for validity of MR estimators.…”