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

Abstract

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<sup>-5</sup>) 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<sup>-5</sup>) using evidence of genotype-specific expression. Where this was observed we selected genes for follow-up investigation and hereby identified<i> SPATS2L </i>and <i>KCTD18 </i>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 <i>RPL8</i>, <i>HSD17B12</i> and <i>PEPD</i> displaying effects on cell proliferation consistent with genetic association and gene expression findings. In conclusion findings presented herein identify<i> SPATS2L,</i> <i>KCTD18, RPL8</i>, <i>HSD17B12,</i> and <i>PEPD</i> of potential importance in controlling fat cell numbers (plasticity), the size of body fat and diabetes risk.