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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.
Monday,2015-03-09 16:27 America/Los_Angeles — zdrager
| Title | 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. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | Peters, U, North, KE, Sethupathy, P, Buyske, S, Haessler, J, Jiao, S, Fesinmeyer, MD, Jackson, RD, Kuller, LH, Rajkovic, A, Lim, U, Cheng, I, Schumacher, F, Wilkens, L, Li, R, Monda, K, Ehret, G, Nguyen, K-DH, Cooper, R, Lewis, CE, Leppert, M, Irvin, MR, C Gu, C, Houston, D, Bůzková, P, Ritchie, M, Matise, TC, Le Marchand, L, Hindorff, LA, Crawford, DC, Haiman, CA, Kooperberg, C |
| Journal | PLoS Genet |
| Volume | 9 |
| Issue | 1 |
| Pagination | e1003171 |
| Date Published | 2013 |
| ISSN | 1553-7404 |
| Keywords | Adaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Body Mass Index, Chromosome Mapping, Continental Population Groups, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Obesity, Proteins |
| Abstract | <p>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.</p> |
| DOI | 10.1371/journal.pgen.1003171 |
| Alternate Journal | PLoS Genet. |
| PubMed ID | 23341774 |
| PubMed Central ID | PMC3547789 |
| Grant List | 1K99DK091318-01 / DK / NIDDK NIH HHS / United States 24152 / / PHS HHS / United States 32100-2 / / PHS HHS / United States 32105-6 / / PHS HHS / United States 32108-9 / / PHS HHS / United States 32111-13 / / PHS HHS / United States 32115 / / PHS HHS / United States 32118-32119 / / PHS HHS / United States 32122 / / PHS HHS / United States 42107-26 / / PHS HHS / United States 42129-32 / / PHS HHS / United States 44221 / / PHS HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States N01WH22110 / WH / WHI NIH HHS / United States P01CA33619 / CA / NCI NIH HHS / United States R01 CA63 / CA / NCI NIH HHS / United States R37CA54281 / CA / NCI NIH HHS / United States U01 HG004790 / HG / NHGRI NIH HHS / United States U01CA136792 / CA / NCI NIH HHS / United States U01CA98758 / CA / NCI NIH HHS / United States U01HG004790 / HG / NHGRI NIH HHS / United States U01HG004798 / HG / NHGRI NIH HHS / United States U01HG004801 / HG / NHGRI NIH HHS / United States U01HG004802 / HG / NHGRI NIH HHS / United States U01HG004803 / HG / NHGRI NIH HHS / United States |