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

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.

Figure 1. Association results (p-values) and correlation structure for all SNPs in the 16q12.2/FTO region and lnBMI among African Americans using rs56137030 to calculate correlation among SNPs (LocusZoom plots).

The top half of each figure has physical position along the x axis, and the −log₁₀ of the meta-analysis p-value on the y-axis. Each dot on the plot represents the p-value of the association for one SNP with lnBMI across all studies. The most significant SNP (rs56137030) is marked as a purple diamond. The color scheme represents the pairwise correlation (r²) for the SNPs across the 16q12.2/FTO region with the most significant SNP (rs56137030). Gray squares indicate that correlation was missing for this p-value because the variant was monomorphic in EA. The bottom half of the figure shows the position of the genes across the region. A and B show the same region and results. The only difference between A and B is that in A correlation with the most significant SNP (rs56137030) was calculated based on EAs, specifically based on data from 65 European Americans (Utah residents with Northern and Western European ancestry from the CEPH collection, CEU) sequenced as part of the 1000 Genomes Project and B correlation was based on 61 African Americans from the South-west (ASW) and sequenced as part of the 1000 Genomes Project.