The missense variation landscape of FTO, MC4R, and TMEM18 in obese children of African Ancestry

Abstract

Objective: Common variation at the loci harboring fat mass and obesity (FTO), melanocortin receptor 4 (MC4R), and transmembrane protein 18 (TMEM18) is consistently reported as being statistically most strongly associated with obesity. Investigations if these loci also harbor rarer missense variants that confer substantially higher risk of common childhood obesity in African American (AA) children were conducted. Design and Methods: The exons of FTO, MC4R, and TMEM18 in an initial subset of our cohort were sequenced, that is, 200 obese (BMI!95th percentile) and 200 lean AA children (BMI 5th percentile). Any missense exonic variants that were uncovered went on to be further genotyped in a further 768 obese and 768 lean (BMI 50th percentile) children of the same ethnicity. Results: A number of exonic variants were observed from our sequencing effort: seven in FTO, of which four were non-synonymous (A163T, G182A, M400V, and A405V), thirteen in MC4R, of which six were non-synonymous (V103I, N123S, S136A, F202L, N240S, and I251L), and four in TMEM18, of which two were non-synonymous (P2S and V113L). Follow-up genotyping of these missense variants revealed only one significant difference in allele frequency between cases and controls, namely with N240S in MC4R (Fisher's exact P ¼ 0.0001). Conclusion: In summary, moderately rare missense variants within the FTO, MC4R, and TMEM18 genes observed in our study did not confer risk of common childhood obesity in African Americans except for a degree of evidence for one known loss-of-function variant in MC4R.

Current review of genetics of human obesity: from molecular mechanisms to an evolutionary perspective

“…Several polymorphisms near the MC4R gene have subsequently been found and replicated in various populations of European descents, as well as in Asians (Xi et al 2012), African American (Xi et al 2012), and in children and adolescents (Grant et al 2008;Deliard et al 2013). …”

“…As a case in point, FTO locus have consistently correlated with BMI and risk of obesity in populations of African (Grant et al 2008;Song et al 2008;Hennig et al 2009;Deliard et al 2013), Asian (Chang et al 2008;Hotta et al 2008;Fang et al 2010;Mačeková et al 2012) and Pacific-Islander (Ohashi et al 2007) ancestry. Despite the fact that effect sizes were similar to those observed in white European populations, the risk of allele frequency varies substantially: ~25% in Asian, ~45% in white Europeans and range of ~7 to 18% in African origin (Hassanein et al 2010).…”

“…Most of obesity susceptible genes were found in studies with adults, which prompted an effort to replicate findings in studies with children Albuquerque et al 2013a;Deliard et al 2013). Knowledge of the genetic risk factors of obesity in children could be used as a first step to develop possible prevention measures.…”

“…Knowledge of the genetic risk factors of obesity in children could be used as a first step to develop possible prevention measures. The FTO locus remains the most replicated gene and the strongest gene associated with obesity susceptibility, both in adults and children (Albuquerque et al 2013a;Deliard et al 2013;León-Mimila et al 2013).…”

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

“…FTO RNA demethylase activity has been linked with regulating dopamine signaling (7), ghrelin production (8), and adipogenesis (9). Nevertheless, nonsynonymous variants in FTO are found equally in obese and lean individuals, suggesting that FTO protein itself may not be the sole cause for the association of the FTO locus with obesity in humans (10)(11)(12). Claussnitzer et al (5) proposed a mechanism in which obesity-risk alleles of rs1421085 in human mesenchymal adipocyte progenitors result in decreased "beiging" (thermogenic potential) of new adipocytes.…”