Multi-ethnic fine-mapping of 14 central adiposity loci

Abstract

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowing the signals remains necessary. Twelve of 14 loci identified in GIANT EA samples retained strong associations with WHR in our joint EA/individuals of African Ancestry (AA) analysis (log-Bayes factor >6.1). Trans-ethnic analyses at five loci (TBX15-WARS2, LYPLAL1, ADAMTS9, LY86 and ITPR2-SSPN) substantially narrowed the signals to smaller sets of variants, some of which are in regions that have evidence of regulatory activity. By leveraging varying linkage disequilibrium structures across different populations, single-nucleotide polymorphisms (SNPs) with strong signals and narrower credible sets from trans-ethnic meta-analysis of central obesity provide more precise localizations of potential functional variants and suggest a possible regulatory role. Meta-analysis results for WHR were obtained from 77 167 EA participants from GIANT and 23 564 AA participants from the African Ancestry Anthropometry Genetics Consortium. For fine mapping we interrogated SNPs within ± 250 kb flanking regions of 14 previously reported index SNPs from loci discovered in EA populations by performing trans-ethnic meta-analysis of results from the EA and AA meta-analyses. We applied a Bayesian approach that leverages allelic heterogeneity across populations to combine meta-analysis results and aids in fine-mapping shared variants at these locations. We annotated variants using information from the ENCODE Consortium and Roadmap Epigenomics Project to prioritize variants for possible functionality.

Figure 1.

Regional plot of loci LYPLAL1 and ADAMTS9. The top panel is obtained from the trans-ethnic meta-analysis result with HapMAP II YRI LD information. The middle panel classifies variants based on whether they are included in the none, either or both of CSs. The red points represent variants retained in both credible regions constructed using EA and trans-ethnic samples; yellow and green points represent variants retained in CSs constructed using EA and trans-ethnic samples, separately; the gray points represents variants which do not fall in any CS.The bottom panel is from EA sample only analysis with HapMap II CEU linkage disequilbrium information. (A) Regional plot of loci LYPLAL1 (Chr1:217 413 815–217 452 830). There are eight SNPs commonly shared by the CSs obtained from EA-only and EA + AA. Fifteen additional SNPs are included in the EA-only derived CS while no additional SNP is included in the EA + AA-derived CS. The length change from 148 141 to 27 409 bp for EA-only and EA + AA derived CSs, respectively. The LD surrounding the original index SNP is much stronger in CEU compared with that in YRI. In addition, few SNPs with high LD with the index SNP in both populations have enhanced association signals and the LD block with the index SNP is much narrower in YRI samples, leading to a much narrower CS in trans-ethnic analysis and dropping 15 variants from EA-derived CS. (B). Regional plot of loci ADAMTS9 (Chr3:64 575 591–64 648 405). There are 7 SNPs commonly shared by the CSs obtained from EA-only and EA + AA. Six additional SNPs are included in the EA-only derived CS while no additional SNP is included in the EA + AA-derived CS. The length change from 30 676 to 8669 bp for EA-only and EA + AA derived CSs, respectively. Neither CEU nor YRI have strong LD for many variants surrounding the original index SNPs; however, the variants with strong LD with index SNP are within a narrow region in both samples of ancestries (narrower in YRI than in CEU). The association signals are highly enhanced and association signals for those top variants are more distinguishable in trans-ethnic analysis compared with EA sample only analysis. These lead to the dropping of six variants from EA-derived CS to form a more compact and narrower trans-ethnic analysis derived CS.

Figure 2.

CS SNPs at LYPLAL1 in regions with evidence of regulatory activity in distinct tissues UCSC genome browser signal enrichment tracks from regulatory datasets with elements overlapping rs1415293 (left-most box; bone and brain) and rs2820446 (right-most box; blood) are shown.