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Genome-wide Association Study Identifies Genetic Loci Associated with Fat Cell Number and Overlap with Genetic Risk Loci For Type 2 Diabetes

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posted on 23.03.2022, 20:58 authored by Agné Kulyté, Alisha Aman, Rona J.Strawbridge, Peter Arner, Ingrid A. Dahlman
Interindividual differences in generation of new fat cells determine body fat and type 2 diabetes risk. We utilized the GENiAL cohort, which consists of participants who have undergone abdominal adipose biopsy, to perform a genome-wide association study (GWAS) of fat cell number (n=896). Candidate genes from the genetic study were knocked down by siRNA in human adipose derived stem cells. We report 318 SNPs and 17 genetic loci displaying suggestive (p<1x10-5) association with fat cell number. Two loci pass threshold for GWAS-significance, on chromosome 2 (lead SNP rs149660479-G) and 7 (rs147389390-deletion). We filtered for fat cell number-associated SNPs (p<1.00x10-5) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified SPATS2L and KCTD18 as regulators of cell proliferation consistent with the genetic data. Furthermore, 30 reported type 2 diabetes-associated SNPs displayed nominal and consistent associations with fat cell number. Functional follow up of candidate genes identified RPL8, HSD17B12 and PEPD displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion findings presented herein identify SPATS2L, KCTD18, RPL8, HSD17B12, and PEPD of potential importance in controlling fat cell numbers (plasticity), the size of body fat and diabetes risk.

Funding

RJS is supported by the University of Glasgow Lord Kelvin/Adam Smith Fellowship. ID is supported by the Strategic Research Program in Diabetes at Karolinska Institutet (Genetic and long-term epigenetic studies of changes in adipose function), Swedish Research Council (2019-00997), Novo Nordisk foundation (NNF200C0063582), and the Swedish Diabetes Association (DIA2019-407). The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the paper for publication.

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