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.
Highlights
The association between variants in the fat mass and obesity associated (FTO) gene on chromosome 16q12.2 and body mass index (BMI) is well-established in populations of European descent
Genetic variants within the fat mass– and obesity-associated (FTO) gene are associated with increased risk of obesity
To better understand which specific genetic variant(s) in this genetic region is associated with obesity risk, we attempt to genotype or impute all known genetic variants in the region and test for association with body mass index as a measurement of obesity in over 20,000 African Americans
Summary
The association between variants in the fat mass and obesity associated (FTO) gene on chromosome 16q12.2 and body mass index (BMI) is well-established in populations of European descent. While several studies showed an association between FTO SNPs and obesity-related phenotypes in Hispanic [5,6,18,19] and Asian populations [20,21,22,23,24,25,26], studies of African or African American (AA) subjects showed limited support for some of the most consistent FTO GWAS findings initially identified in subjects of European descent [2,5,6,14,18,19,27,28,29,30,31,32] This lack of generalization in AA may be attributable to the lower levels of linkage disequilibrium (LD) with the underlying functional variant(s) at the 16q12.2/FTO locus, as compared with European Americans (EAs). African populations are suited for these studies because the LD pattern between SNPs tends to be substantially weaker than in other ancestral groups, as has been demonstrated for the FTO gene [30] This process can reduce the number of potential functional variants for follow-up molecular investigation [33]. We used the Metabochip as genotyping platform [35], which included all suitable SNPs discovered in the 1000 Genomes Project Pilot 1 for the 16q12.2/FTO region and led to successfully genotyping of over
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
