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
T2 - Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study
AU - Peters, Ulrike
AU - North, Kari E.
AU - Sethupathy, Praveen
AU - Buyske, Steve
AU - Haessler, Jeff
AU - Jiao, Shuo
AU - Fesinmeyer, Megan D.
AU - Jackson, Rebecca D.
AU - Kuller, Lew H.
AU - Rajkovic, Aleksandar
AU - Lim, Unhee
AU - Cheng, Iona
AU - Schumacher, Fred
AU - Wilkens, Lynne
AU - Li, Rongling
AU - Monda, Keri
AU - Ehret, Georg
AU - Nguyen, Khanh Dung H.
AU - Cooper, Richard
AU - Lewis, Cora E.
AU - Leppert, Mark
AU - Irvin, Marguerite R.
AU - Gu, C. Charles
AU - Houston, Denise
AU - Buzkova, Petra
AU - Ritchie, Marylyn
AU - Matise, Tara C.
AU - Le Marchand, Loic
AU - Hindorff, Lucia A.
AU - Crawford, Dana C.
AU - Haiman, Christopher A.
AU - Kooperberg, Charles
PY - 2013/1
Y1 - 2013/1
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=84873504695&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003171
DO - 10.1371/journal.pgen.1003171
M3 - Article
C2 - 23341774
AN - SCOPUS:84873504695
SN - 1553-7390
VL - 9
JO - PLoS genetics
JF - PLoS genetics
IS - 1
M1 - e1003171
ER -