Osteoporosis- and obesity-risk interrelationships: An epigenetic analysis of GWAS-derived SNPs at the developmental geneTBX15

Abstract

A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighborhood to prioritize this region's best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15. Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.Recently, whole-genome profiles of epigenetics features, such as promoter-type or enhancer-type chromatin, have been used to help discriminate likely causal variants from bystander SNPs in high LD with them (15,17,18).GWAS SNPs, including those for obesity-related traits (9), are generally enriched in enhancer chromatin or promoter regions (14,15,19,20). In GWAS of (mostly) individuals of European ancestry (EUR) (13, 21) or of East Asians (6, 11), SNPs linked to TBX15 were identified as significantly associated with BMI, WHRadjBMI or WCadjBMI in mixed sex populations, or separately in women or men (Supplementary Material, Table S1). TBX15 codes for a Tbox transcription factor (TF) that may be involved in various aspects of adipose development and maintenance (22)(23)(24) and is known to be important in formation of the skeletal system (25,26). SNPs in or near TBX15 are significantly associated not only with obesity traits but also with estimated heel bone mineral density (eBMD), a useful indicator of hip and non-spine fractures that is used as a proxy for osteoporosis risk (27).Our study of the relationships in GWAS of TBX15 to both adipose and bone biology provides novel insights into the developmental relationships between two related tissue lineages converging on one gene. Both adipocytes and oste...