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Genetics of Body Fat Distribution: Comparative Analyses in Populations with European, Asian and African Ancestries.

ABSTRACT: Preferential fat accumulation in visceral vs. subcutaneous depots makes obese individuals more prone to metabolic complications. Body fat distribution (FD) is regulated by genetics. FD patterns vary across ethnic groups independent of obesity. Asians have more and Africans have less visceral fat compared with Europeans. Consequently, Asians tend to be more susceptible to type 2 diabetes even with lower BMIs when compared with Europeans. To date, genome-wide association studies (GWAS) have identified more than 460 loci related to FD traits. However, the majority of these data were generated in European populations. In this review, we aimed to summarize recent advances in FD genetics with a focus on comparisons between European and non-European populations (Asians and Africans). We therefore not only compared FD-related susceptibility loci identified in three ethnicities but also discussed whether known genetic variants might explain the FD pattern heterogeneity across different ancestries. Moreover, we describe several novel candidate genes potentially regulating FD, including NID2, HECTD4 and GNAS, identified in studies with Asian populations. It is of note that in agreement with current knowledge, most of the proposed FD candidate genes found in Asians belong to the group of developmental genes.

SUBMITTER: Sun C

PROVIDER: S-EPMC8228180 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Project description:Several studies have evaluated computational methods that infer the haplotypes from population genotype data in European cattle populations. However, little is known about how well they perform in African indigenous and crossbred populations. This study investigates: (1) global and local ancestry inference; (2) heterozygosity proportion estimation; and (3) genotype imputation in West African indigenous and crossbred cattle populations. Principal component analysis (PCA), ADMIXTURE, and LAMP-LD were used to analyse a medium-density single nucleotide polymorphism (SNP) dataset from Senegalese crossbred cattle. Reference SNP data of East and West African indigenous and crossbred cattle populations were used to investigate the accuracy of imputation from low to medium-density and from medium to high-density SNP datasets using Minimac v3. The first two principal components differentiated Bos indicus from European Bos taurus and African Bos taurus from other breeds. Irrespective of assuming two or three ancestral breeds for the Senegalese crossbreds, breed proportion estimates from ADMIXTURE and LAMP-LD showed a high correlation (r ≥ 0.981). The observed ancestral origin heterozygosity proportion in putative F1 crosses was close to the expected value of 1.0, and clearly differentiated F1 from all other crosses. The imputation accuracies (estimated as correlation) between imputed and the real data in crossbred animals ranged from 0.142 to 0.717 when imputing from low to medium-density, and from 0.478 to 0.899 for imputation from medium to high-density. The imputation accuracy was generally higher when the reference data came from the same geographical region as the target population, and when crossbred reference data was used to impute crossbred genotypes. The lowest imputation accuracies were observed for indigenous breed genotypes. This study shows that ancestral origin heterozygosity can be estimated with high accuracy and will be far superior to the use of observed individual heterozygosity for estimating heterosis in African crossbred populations. It was not possible to achieve high imputation accuracy in West African crossbred or indigenous populations based on reference data sets from East Africa, and population-specific genotyping with high-density SNP assays is required to improve imputation.

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Genetics of Body Fat Distribution: Comparative Analyses in Populations with European, Asian and African Ancestries.

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