Abstract
The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.
Highlights
Waist – hip ratio, a measure of body fat distribution, is associated with metabolic consequences independent of overall adiposity as measured by body mass index (BMI) (1 – 3)
The Genetic Investigation of Anthropometric Traits (GIANT) consortium previously reported 14 loci associated with waist – hip ratio adjusted for BMI, age, age2 and sex [waist-to-hip ratio (WHR)] in studies of European Ancestry (EA) [5]
Eight of the 95% credible sets (CSs) obtained from trans-ethnic association analyses generated shorter CSs length ranging from 4 to 94% length reduction (DNM3-PIGC, NFE2L3, LY86, LYPLAL1, ADAMTS9, ITPR2-SSPN, RSPO3 and TBX15-WARS2) compared with the sets based on EA samples only (Fig. 1 and Supplementary Material, Fig. S1) and five (LY86, LYPLAL1, ADAMTS9, ITPR2-SSPN and TBX15-WARS2) of them have .25% length reduction
Summary
Waist – hip ratio, a measure of body fat distribution, is associated with metabolic consequences independent of overall adiposity as measured by body mass index (BMI) (1 – 3). Evidence has indicated that body fat distribution is partially determined by genetic factors with age- and BMI-adjusted heritability estimates for waist – hip ratio ranging from 36– 61% [4]. The Genetic Investigation of Anthropometric Traits (GIANT) consortium previously reported 14 loci associated with waist – hip ratio adjusted for BMI, age, age and sex [waist-to-hip ratio (WHR)] in studies of European Ancestry (EA) [5]. We conducted a similar genome-wide association analysis in African Ancestry (AA) studies jointly from the African Ancestry Anthropometry Genetics (AAAG) Consortium, identifying one WHR-associated locus [6].
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