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.

Distinct DNA methylation signatures associated with blood lipids as exposures or outcomes among survivors of childhood cancer: a report from the St. Jude lifetime cohort

“…CYTH3 gene encodes Cytohesin-3, which is essential for insulin receptor signaling and body fat regulation via lipid excretion [ 22 ]. Among novel genes (i.e., not genes with nearby lipid-associated CpGs in EWAS Catalog), four of them were reported as high-confidence genes that play a role in lipid levels, including LPIN2 (near cg07616376 associated with TG exposure among EA), SCARB1 (near cg08458758 associated with TG outcome among EA), MSI2 (near cg21376908 associated with TG exposure among AA), and SSBP3 (near cg16411101 associated with LDL and TC outcome among AA) [ 23 ].…”

Sex and statin-related genetic associations at the PCSK9 gene locus: results of genome-wide association meta-analysis

“…Finally, we tested for co-localization between our PCSK9 signals and other traits to identify possible related outcomes. This included lipid traits [ 8 ], coronary artery disease (CAD) [ 44 ], bilirubin levels (GCST90019521) [ 45 ] and sleep duration (GCST007561) [ 46 ], as PCSK9 is linked to the circadian rhythm.…”

“…Sexual dimorphisms are common in lipid metabolism, and PCSK9 also exhibits sex-differential behavior with women having higher circulating PCSK9 concentrations than men [ 6 , 7 ]. While large-scale sex-stratified genome-wide association meta-analyses (GWAMA) were already performed for the common lipid traits such as: total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and non-HDL-C [ 8 ], so far there was no GWAS on stratified PCSK9 levels to the best of our knowledge.…”

Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases

“…During aging, changes in the levels of neurotransmitters and hormones seem to make the brain more prone to suffer cerebrovascular accidents and white matter lesions, leading to memory impairment and dementia ( Jett et al, 2022 ; Kanoni et al, 2022 ; Hogervorst et al, 2023 ; Kerstens et al, 2023 ). Cognitive impairment results from complex mechanisms affecting the brain’s function during aging.…”