UNIGE document Scientific Article
previous document  unige:40634  next document
add to browser collection
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

Authors
Peters, Ulrike
North, Kari E
Sethupathy, Praveen
Buyske, Steve
Haessler, Jeff
Jiao, Shuo
Fesinmeyer, Megan D
Jackson, Rebecca D
show hidden authors show all authors [1 - 32]
Published in PLOS Genetics. 2013, vol. 9, no. 1, p. e1003171
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.
Keywords Adaptor Proteins, Signal Transducing/geneticsAdultAfrican Americans/geneticsAgedAged, 80 and overAllelesBody Mass IndexChromosome MappingContinental Population Groups/geneticsEuropean Continental Ancestry Group/geneticsFemaleGenetic Predisposition to DiseaseGenome-Wide Association StudyHumansLinkage DisequilibriumMaleMetagenomicsMiddle AgedObesity/geneticsProteins/genetics
Identifiers
PMID: 23341774
Full text
Article (Published version) (523 Kb) - public document Free access
Structures
Research group Traits génétiques complexes (901)
Citation
(ISO format)
PETERS, Ulrike et al. 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. In: PLOS Genetics, 2013, vol. 9, n° 1, p. e1003171. https://archive-ouverte.unige.ch/unige:40634

223 hits

61 downloads

Update

Deposited on : 2014-10-02

Export document
Format :
Citation style :