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Abstract
Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants.
| Item Type: | Journal Article |
|---|---|
| Publication: | Nature Genetics |
| Publisher: | Nature Publishing Group |
| Additional Information: | The copyright for this article belongs to the Author(s). |
| Keywords: | adiponectin; protein; lipid; protein, ACVR1C gene; adipogenesis; African; angiogenesis; ANGPTL4 gene; Article; bioinformatics; body fat distribution; body mass; bone development; coding; DAGLB gene; DNAH10 gene; Drosophila; East Asian; European; exome; expression quantitative trait locus; FGFR2 gene; gene; gene frequency; gene knockdown; genetic trait; genetic variability; genotype; glucose homeostasis; Hispanic; human; insulin blood level; lipid homeostasis; meta analysis; MLXIPL gene; nonhuman; phenotype; PLXND1 gene; priority journal; RAPGEF3 gene; recessive inheritance; RNA splicing; RREB1 gene; sex difference; South Asian; TBX15 gene; triacylglycerol level; waist hip ratio; white adipose tissue; animal; body fat distribution; case control study; female; genetic predisposition; genetic variation; genetics; genome-wide association study; homeostasis; male; procedures; risk factor, Animals; Body Fat Distribution; Body Mass Index; Case-Control Studies; Drosophila; Exome; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Homeostasis; Humans; Lipids; Male; Proteins; Risk Factors; Waist-Hip Ratio |
| Department/Centre: | Autonomous Societies / Centres > Centre for Brain Research |
| Date Deposited: | 31 Oct 2022 11:22 |
| Last Modified: | 31 Oct 2022 11:22 |
| URI: | https://eprints.iisc.ac.in/id/eprint/77714 |
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