Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy

Natalie DeForest, Yuqi Wang, Zhiyi Zhu, Jacqueline S. Dron, Ryan Koesterer, Pradeep Natarajan, Jason Flannick, Tiffany Amariuta, Gina M. Peloso and Amit R. Majithia ()
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Natalie DeForest: University of California San Diego
Yuqi Wang: University of California San Diego
Zhiyi Zhu: University of California San Diego
Jacqueline S. Dron: Massachusetts General Hospital
Ryan Koesterer: Broad Institute of MIT and Harvard
Pradeep Natarajan: Massachusetts General Hospital
Jason Flannick: Broad Institute of MIT and Harvard
Tiffany Amariuta: University of California San Diego
Gina M. Peloso: Boston University School of Public Health
Amit R. Majithia: University of California San Diego

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.

Date: 2024
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DOI: 10.1038/s41467-024-52105-y

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