Identification of lipid quantitative trait loci linked with cardiometabolic disease in Asian Indians and Europeans: A genome-wide association study and mendelian randomization.

Abstract

Genetic mechanisms that predispose people to type 2 diabetes (T2D) and cardiovascular disease (CVD) remain poorly understood, partly because of a lack of sufficient data on non-European ethnic groups. Extending these evaluations to diverse cohorts is essential for gaining insights into the molecular pathways involved in disease development among human populations. In this study, we aimed to evaluate the genetic connection between the human lipidome and cardiometabolic disorders. We conducted a metabolite genome-wide association study (mGWAS) in a Punjabi population from India, along with multi-layer replication studies using the UK Biobank and other independent European and non-European cohorts. We performed mGWAS using 516 lipid metabolites in 3,000 Punjabi Sikh individuals, and validation was performed in 1.13M Europeans and 15K individuals from Asian Indian ancestry using independent cohorts of the UK Biobank, GeneRISK, DIAMANT, PROMIS, and other studies. We identified 609 SNP-metabolite associations representing 236 SNP-metabolite pairs that attained genome-wide significance (p </= 5 × 10-8). Of the 36 SNP-lipid metabolite signals that survived multiple testing correction (p </= 1.92 × 10-10), 33 associations were not reported before, and 3 associations were confirmed to be ancestry-specific. Using colocalization analysis, polygenic risk scores, and mendelian randomization approaches, we identified a causal association of LPC O-16:0 with T2D, represented by a lead variant in CD45, a key regulator of T- and B-cell antigen receptor signaling, and is already used as a therapeutic target. Another possible causal relationship of PC 38:4 (C) in protecting against coronary artery disease risk in Asian Indians, attributed to a variant in the untranslated region in the FADS1/2 genes, may be specific to ancestry and/or could not be confirmed in Europeans because of extensive pleiotropy in this region. The main limitation of this study was the absence of an independent validation cohort of Asian Indians from India. The mGWAS of Asian Indians offers new insights into the diverse molecular origins of cardiometabolic diseases and suggests potential pathways for innovative treatments. Our findings highlight the need for additional research on human lipidomics to better understand the downstream effects of the genome and its impact on cardiometabolic health.