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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.

TitleA 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 TypeJournal Article
Year of Publication2013
AuthorsPeters 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, Gu CC, Houston D, Bůžková P, Ritchie M, Matise TC, Le Marchand L, Hindorff LA, Crawford DC, Haiman CA
Secondary AuthorsKooperberg C
JournalPLoS Genet
Volume9
Issue1
Paginatione1003171
Date Published2013
ISSN1553-7404
KeywordsAdaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 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

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.

DOI10.1371/journal.pgen.1003171
Alternate JournalPLoS Genet
PubMed ID23341774
PubMed Central IDPMC3547789
Grant List32105-6 / / PHS HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
42107-26 / / PHS HHS / United States
32115 / / PHS HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
32100-2 / / PHS HHS / United States
24152 / / PHS HHS / United States
42129-32 / / PHS HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
1K99DK091318-01 / DK / NIDDK NIH HHS / United States
32118-32119 / / PHS HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
32108-9 / / PHS HHS / United States
U01HG004801 / HG / NHGRI NIH HHS / United States
R37CA54281 / CA / NCI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
32122 / / PHS HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
44221 / / PHS HHS / United States
32111-13 / / PHS HHS / United States
P01CA33619 / CA / NCI NIH HHS / United States
R01 CA63 / CA / NCI NIH HHS / United States