TY - JOUR T1 - A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study. JF - PLoS Genet Y1 - 2013 A1 - Peters, Ulrike A1 - North, Kari E A1 - Sethupathy, Praveen A1 - Buyske, Steve A1 - Haessler, Jeff A1 - Jiao, Shuo A1 - Fesinmeyer, Megan D A1 - Jackson, Rebecca D A1 - Kuller, Lew H A1 - Rajkovic, Aleksandar A1 - Lim, Unhee A1 - Cheng, Iona A1 - Schumacher, Fred A1 - Wilkens, Lynne A1 - Li, Rongling A1 - Monda, Keri A1 - Ehret, Georg A1 - Nguyen, Khanh-Dung H A1 - Cooper, Richard A1 - Lewis, Cora E A1 - Leppert, Mark A1 - Irvin, Marguerite R A1 - Gu, C Charles A1 - Houston, Denise A1 - Bůzková, Petra A1 - Ritchie, Marylyn A1 - Matise, Tara C A1 - Le Marchand, Loïc A1 - Hindorff, Lucia A A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Kooperberg, Charles KW - Adaptor Proteins, Signal Transducing KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Alleles KW - Body Mass Index KW - Chromosome Mapping KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Metagenomics KW - Middle Aged KW - Obesity KW - Proteins AB -

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 × 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23341774?dopt=Abstract ER -