Genome-wide analysis of blood lipid metabolites in over 5,000 South Asians reveals biological insights at cardiometabolic disease loci

Abstract

Background: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. Methods: We characterised the genetic architecture of the human blood lipidome in 5,662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. Results: We identified 359 genetic associations with 255 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 616 genetic associations with 326 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Conclusions: Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Comprehensive genetic analysis of the human lipidome identifies novel loci controlling lipid homeostasis with links to coronary artery disease

“…Prior studies examined lipid phenotypes that were mixtures of similar, but distinct species; lacked structural characterization of lipid species; or were contaminated through isotopic overlap. Many of the associations between lipid species and prototypical lipid regulating genes observed in our study -such as FADS1/FADS2, APOE and LDLR -have been reported in earlier GWAS [7][8][9][10][11][12][13][14][15]17,23 . With our expanded lipidomic profile, we have built on these earlier studies, identifying many new loci associated with lipid species and classes.…”

“…Our high resolution genome-wide association analyses of the human lipidome has identified 737 independent genomic regions associated with lipid metabolism, of which 509 represent novel genetic loci. This is a substantial increase over previous studies with similar or larger sample sizes 7,10,23 . Our expanded lipidomic platform utilises extensive chromatographic separation to increase the diversity of measured lipid species and distinguish lipid isomers and isotopes over those measured in previous studies.…”

Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistanis and Bangladeshis

“…The copyright holder for this preprint this version posted June 24, 2021. ; https://doi.org/10.1101/2021.06.22.21259323 doi: medRxiv preprint 29 restricted their comparisons to the index SNP identified in the GWAS, which does not take LD into account [34][35][36] . A recent study compared genetic determinants of >200 lipid metabolites in 5,000 South Asians from Pakistan and 13,000 Europeans and found high overlap in the detected associations 57 . Using a new method, our paper goes further by empirically demonstrating that, in most cases where loci do not replicate, it is due to lack of power.…”