Genetics of Obesity in Diverse Populations

Abstract

Purpose of review: The prevalence of obesity continues to rise, fueling a global public health crisis characterized by dramatic increases in type 2 diabetes, cardiovascular disease, and many cancers. In the USA, several minority populations, who bear much of the obesity burden (47% in African Americans and Hispanic/Latinos, compared to 38% in European descent groups), are particularly at risk of downstream chronic disease. Compounding these disparities, most genome-wide association studies (GWAS)-including those of obesity-have largely been conducted in populations of European or East Asian ancestry. In fact, analysis of the GWAS Catalog found that while the proportion of participants of non-European or non-Asian descent had risen from 4% in 2009 to 19% in 2016, African-ancestry participants are still just 3% of GWAS, Hispanic/Latinos are < 0.5%, and other ancestries are < 0.3% or not represented at all. This review summarizes recent developments in obesity genomics in US minority populations, with the goal of reducing obesity health disparities and improving public health programs and access to precision medicine.

Recent findings: GWAS of populations with the highest burden of obesity are essential to narrow candidate variants for functional follow-up, to identify additional ancestry-specific variants that contribute to individual genetic susceptibility, and to advance both public health and precision medicine approaches to obesity. Given the global public health burden posed by obesity and downstream chronic conditions which disproportionately affect non-European populations, GWAS of obesity-related traits in diverse populations is essential to (1) locate causal variants in GWAS-identified regions through fine mapping, (2) identify variants which influence obesity across ancestries through generalization, and (3) discover novel ancestry-specific variants which may be low frequency in European populations but common in other groups. Recent efforts to expand obesity genomic studies to understudied and underserved populations, including AAAGC, PAGE, and HISLA, are working to reduce obesity health disparities, improve public health, and bring the promise of precision medicine to all.

Keywords: GWAS; Health disparities; Obesity; Precision medicine.

Figure 1:

Locuszoom plots of the MAP2K5 locus using discovery results for established loci that reached genome-wide significance for BMI in men and women combined in the AAAGC [•]. Plots use EUR and AFR LD from the 1000 Genomes phase 1 reference panel. In each plot, the most significant variant in AAAGC within a 1Mb regional locus is highlighted. P-values for all variants including the most significant variant are based on the African ancestry discovery phase only. (Reproduced from Ng MCY, Graff M, Lu Y, et al (2017) Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium. PLoS Genet 13:e1006719. This work is made available under the Creative Commons CC0 public domain dedication) [••].

Figure 2:

Locus zoom plots of chromosome 5 for body mass index (sexes combined) and WHRadjBMI (women only) in the pooled PAGE II study.[•] Left panel: Lead BMI SNP rs76493495 and 1 MB surrounding region, body mass index was adjusted for age, sex, PC1–10, study, study center, and ancestry. Right panel: Lead WHRadjBMI SNP rs10477191 and 1 MB surrounding region, waist-hip ratio was first adjusted for BMI, and then the residuals were adjusted for age, PC-10, study, study center, and ancestry. (Reproduced from Wojcik G, Graff M, Nishimura KK, et al (2017) Genetic diversity turns a new PAGE in our understanding of complex traits. bioRxiv doi:10.1101/188094. This work is made available under the creativecommons.org/licenses/by-nd/4.0) [••].