Abstract MP84: Trans-ethnic Meta-analysis of Exome Chip Data Reveals Novel Low-frequency Variants Contributing to Central Adiposity
Central adiposity is a leading risk factor for cardiovascular disease, and genetic factors contribute both to fat distribution, measured as waist-to-hip ratio adjusted for BMI (WHRa), and to differences in central adiposity prevalence. To date, 49 loci have been associated with WHRa, based on studies of common [minor allele frequency (MAF) ≥5%] single nucleotide variants (SNVs), primarily in European descent populations. Our aim was to identify low frequency (LFV: MAF <5%) and rare (RV: MAF <1%) coding variants associated with WHRa using Exome-Chip data from 344,369 individuals of European (84%), South Asian (8%), African (5%), East Asian(2%), and Hispanic/Latino (1%) ancestry. We performed fixed effects meta-analyses of study-specific WHRa associations stratified by sex and ancestry and then combined across strata for both SNV and gene-based results. We used a strict definition of variants annotated as damaging by 5 algorithms to perform gene-based analyses using the sequence kernel association test (SKAT). Analyses included up to 284,499 SNVs (218,195 with MAF<5%), and 15,063 genes with at least one SNV that met our inclusion criteria. Five LFVs reached chip-wide significance (CWS: P<2.5E-7) in our all ancestry sex-combined analyses, including one novel non-synonymous LFV in RAPGEF3 [MAF=0.01, β (SE) = -0.09 (0.012), P=1.28E-13]. In addition, one novel RV reached CWS in men for UGGT2 [MAF<0.01, β (SE) = -0.142 (0.025), P=9.71E-9], and one RV reached CWS in women for ACVR1C [MAF<0.01, β (SE) = -0.09 (0.018), P=1.09E-7]. Gene-based analyses identified RAPGEF3 (P=1.18E-11) as significantly associated with WHRa in the all ancestry sex combined analyses after correction for multiple tests (P<2.5E-6), though conditional analysis revealed that this result is driven by the top SV identified in this region. RAPGEF3 also shows a significant association (p=4.68E-12) in all ancestry, sex combined gene-based analysis of BMI. RAPGEF3 is expressed in subcutaneous and visceral adipose tissue, and has been implicated in insulin regulation. RAPGEF3 plays a role in the GLP1 pathway, which controls insulin secretion in response to blood glucose concentration. Our results highlight the importance of large-scale genomic studies for identifying LFV and RV influencing central fat distribution. Understanding these genetic effects may provide insights into the progression of central adiposity and highlight potential population-specific variants that increase susceptibility.
Author Disclosures: K.L. Young: None. A. Justice: None. T. Karaderi: None. H. Highland: None. M. Graff: None. V. Turcot: None. P. Auer: None. N. Heard-Costa: None. C. Schurmann: None. Y. Lu: None. D. Pasko: None. L. Cupples: None. C. Fox: None. T. Winkler: None. R. Scott: None. M. McCarthy: None. K. Mohlke: None. R. Loos: None. K. North: None. I. Borecki: None. C. Lindgren: None.
- © 2016 by American Heart Association, Inc.