Fine mapping of the association with obesity at the FTO locus in African-derived populations

Abstract

Genome-wide association studies have identified many common genetic variants that are associated with polygenic traits, and have typically been performed with individuals of recent European ancestry. In these populations, many common variants are tightly correlated, with the perfect or near-perfect proxies for the functional or true variant showing equivalent evidence of association, considerably limiting the resolution of fine mapping. Populations with recent African ancestry often have less extensive and/or different patterns of linkage disequilibrium (LD), and have been proposed to be useful in fine-mapping studies. Here, we strongly replicate and fine map in populations of predominantly African ancestry the association between variation at the FTO locus and body mass index (BMI) that is well established in populations of European ancestry. We genotyped single nucleotide polymorphisms that are correlated with the signal of association in individuals of European ancestry but that have varying degrees of correlation in African-derived individuals. Most of the variants, including one previously proposed as functionally important, have no significant association with BMI, but two variants, rs3751812 and rs9941349, show strong evidence of association (P = 2.58 x 10(-6) and 3.61 x 10(-6) in a meta-analysis of 9881 individuals). Thus, we have both strongly replicated this association in African-ancestry populations and narrowed the list of potentially causal variants to those that are correlated with rs3751812 and rs9941349 in African-derived populations. This study illustrates the potential of using populations with different LD patterns to fine map associations and helps pave the way for genetically guided functional studies at the FTO locus.

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

“…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).…”

Hypomorphism of Fto and Rpgrip1l causes obesity in mice

“…Cohorts of individuals of African descent have been examined by others in an effort to reduce the size of the FTO interval implicated in adiposity (23)(24)(25). In these studies, rs8050136 (minor allele frequency = 0.34), and the landmark SNP rs9939609 first reported by McCarthy (1), were associated weakly or not at all with BMI in subjects of African descent.…”

Variation in sequence and expression of the avian FTO, and association with glucose metabolism, body weight, fatness and body composition in chickens

“…The fat mass and obesity-associated gene (FTO) was recently identified as an obesity candidate gene by three largescale and independent genome-wide association studies, which strongly associated several single nucleotide polymorphisms (SNPs) of FTO with obesity-related traits, including body mass index, hip circumference and body weight. 1 --3 Significant associations between FTO and obesity were independently replicated in many other studies of different populations, including Korean, 4 Japanese, 5 Malay, 6 Chinese, 6,7 Belgian, 8 British, 9,10 Dutch, 11,12 German, 13 Finnish, 14 French, 15 Swedish, 16,17 Caucasian, 18 African 19 and American. 18,20 --22 In mice, FTO deficiency caused postnatal growth retardation and a significant reduction in adipose tissue and lean body mass, 23 and FTO deletion resulted in lesser postnatal growth and lower serum IGF-1 levels.…”