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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

Peters, U and North, KE and Sethupathy, P and Buyske, S and Haessler, J and Jiao, S and Fesinmeyer, MD and Jackson, RD and Kuller, LH and Rajkovic, A and Lim, U and Cheng, I and Schumacher, F and Wilkens, L and Li, R and Monda, K and Ehret, G and Nguyen, KDH and Cooper, R and Lewis, CE and Leppert, M and Irvin, MR and Gu, CC and Houston, D and Buzkova, P and Ritchie, M and Matise, TC and Le Marchand, L and Hindorff, LA and Crawford, DC and Haiman, CA and Kooperberg, C (2013) 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. PLoS Genetics, 9 (1). ISSN 1553-7390

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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 r2>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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Peters, U
North, KE
Sethupathy, P
Buyske, S
Haessler, J
Jiao, S
Fesinmeyer, MD
Jackson, RD
Kuller, LHKullerL@edc.pitt.eduKULLER
Rajkovic, Aalr110@pitt.eduALR110
Lim, U
Cheng, I
Schumacher, F
Wilkens, L
Li, R
Monda, K
Ehret, G
Nguyen, KDH
Cooper, R
Lewis, CE
Leppert, M
Irvin, MR
Gu, CC
Houston, D
Buzkova, P
Ritchie, M
Matise, TC
Le Marchand, L
Hindorff, LA
Crawford, DC
Haiman, CA
Kooperberg, C
Date: 1 January 2013
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 9
Number: 1
DOI or Unique Handle: 10.1371/journal.pgen.1003171
Schools and Programs: Graduate School of Public Health > Epidemiology
School of Medicine > Obstetrics, Gynecology, and Reproductive Sciences
Refereed: Yes
ISSN: 1553-7390
Other ID: NLM PMC3547789
PubMed Central ID: PMC3547789
PubMed ID: 23341774
Date Deposited: 14 Mar 2013 14:30
Last Modified: 04 Feb 2019 19:55
URI: http://d-scholarship.pitt.edu/id/eprint/17722

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