Polygenic obesity

Abstract

A small number of single gene mutations causing human obesity have been identified by molecular genetic analyses; the responsible mutations are rare. The genetic mechanisms involved in the predisposition to obesity in most affected people are polygenic (Locke et al., Nature 518:197–206, 2015). Currently, more than 100 such "polygenes" or "polygenic loci" harboring genetic variants associated with BMI have been identified (Yazdi et al., PeerJ 3:e856, 2015). Each single polygene makes only a small contribution, in the magnitude of a few hundred grams or less, to the development of obesity. A number of such predisposing gene variants (alleles) are found in obese subjects; however, the same alleles, although at a lower frequency, are also found in normal-weight and even lean individuals (Hebebrand et al., Dtsch Arztebl Int. 110:338–44, 2013). Evidently, these alleles can only be identified and validated as obesity-risk alleles by statistical analyses (Locke et al., Nature 518:197–206, 2015). Currently, combined genome-wide association studies (GWAS) on more than 300,000 population-based individuals have been conducted, and meta-analyses of additional GWAS (GWAMA) are under way, which will be based on over 1,000,000 mainly epidemiologically ascertained subjects. Recently, cross-disorder and cross-phenotype analyses have led to the identification of genes that had not been detected by analyses of single disorders/phenotypes alone (Hinney et al., Mol Psychiatry 22:192–201, 2017; Bulik-Sullivan et al., Nat Genet 47:1236–41, 2015). Functional in vitro and in vivo studies of the GWAS-derived polygenes are assumed to lead to a better understanding of the molecular genetic mechanisms involved in body weight regulation. It is a matter of debate if epigenetic markers can be transmitted across generations and can thus explain part of the heritability. Initial genome-wide methylation pattern analyses (Dick et al., Lancet. 383:1990–82014, 2014) and studies on "metastable epialleles" (Kühnen et al., Cell Metab. 24:502-9, 2016) pave the way to a better understanding of epigenetic mechanisms in obesity.