Systematic fine-mapping of association with BMI and type 2 diabetes at the FTO locus by integrating results from multiple ethnic groups

Abstract

Background/objective: The 16q12.2 locus in the first intron of FTO has been robustly associated with body mass index (BMI) and type 2 diabetes in genome-wide association studies (GWAS). To improve the resolution of fine-scale mapping at FTO, we performed a systematic approach consisting of two parts.

Methods: The first part is to partition the associated variants into linkage disequilibrium (LD) clusters, followed by conditional and haplotype analyses. The second part is to filter the list of potential causal variants through trans-ethnic comparison.

Results: We first examined the LD relationship between FTO SNPs showing significant association with type 2 diabetes in Japanese GWAS and between those previously reported in European GWAS. We could partition all the assayed or imputed SNPs showing significant association in the target FTO region into 7 LD clusters. Assaying 9 selected SNPs in 4 Asian-descent populations--Japanese, Vietnamese, Sri Lankan and Chinese (n≤26,109 for BMI association and n≤24,079 for type 2 diabetes association), we identified a responsible haplotype tagged by a cluster of SNPs and successfully narrowed the list of potential causal variants to 25 SNPs, which are the smallest in number among the studies conducted to date for FTO.

Conclusions: Our data support that the power to resolve the causal variants from those in strong LD increases consistently when three distant populations--Europeans, Asians and Africans--are included in the follow-up study. It has to be noted that this fine-mapping approach has the advantage of applicability to the existing GWAS data set in combination with direct genotyping of selected variants.

Figure 1. Plots of SNP–trait association and SNP partitioning for the 16q12.2/FTO region in Japanese (type 2 diabetes, a) and Europeans (type 2 diabetes, b; BMI, c).

Association results for Europeans are drawn from the published studies , . a, b and c each contain three panels. In the top panels, all assayed/imputed SNPs in the GWA scan (that passed the quality control) are plotted with their −log10 (p-values) for type 2 diabetes (a and b) and BMI (c) against chromosome position (in Mb): genotypes are imputed to the HapMap Phase 2 data set. In the second panels, the genomic locations of RefSeq genes with intron and exon structure (NCBI Build 37) are displayed. The third panels show the plots for the intron-1 FTO region, where the associated SNPs are partitioned into seven clusters and colored accordingly (see Methods).

Figure 2. Estimated haplotype phylogeny at the FTO locus.

Haplotypes with frequencies ≥0.05 are demonstrated in the figure, apart from H1-1, H1-2, H1-3, H3-1 and H3-3, which could be generated by recombination. Also see Table 2 and Table S5.

Figure 3. Overlap of SNPs associated with BMI at FTO.

The Venn diagram illustrates the number of SNPs that show association with BMI in any of three ethnic groups. The total number of associated SNPs in individual ethnic groups is listed in parentheses after the ethnic group name.