Abstract
Concern about rising rates of obesity has prompted searches for obesity-related single nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS). Identifying plausible regulatory SNPs is very difficult partially because of linkage disequilibrium. We used an unusual epigenomic and transcriptomic analysis of obesity GWAS-derived SNPs in adipose versus heterologous tissues. From 50 GWAS and 121,064 expanded SNPs, we prioritized 47 potential causal regulatory SNPs (Tier-1 SNPs) for 14 gene loci. A detailed examination of seven loci revealed that four (CABLES1, PC, PEMT, and FAM13A) had Tier-1 SNPs positioned so that they could regulate use of alternative transcription start sites, resulting in different polypeptides being generated or different amounts of an intronic microRNA gene being expressed. HOXA11 and long noncoding RNA gene RP11-392O17.1 had Tier-1 SNPs in their 3′ or promoter region, respectively, and strong preferences for expression in subcutaneous versus visceral adipose tissue. ZBED3-AS1 had two intragenic Tier-1 SNPs, each of which could contribute to mediating obesity risk through modulating long-distance chromatin interactions. Our approach not only revealed especially credible novel regulatory SNPs, but also helped evaluate previously highlighted obesity GWAS SNPs that were candidates for transcription regulation.
Highlights
The rapidly rising rates of obesity are a major concern for public health and increased risk of disease, including type 2 diabetes (T2D), cardiovascular disease, osteoarthritis, certain kinds of cancer, and respiratory problems [1,2]
The prioritization depended on the assumptions that many of the regulatory single nucleotide polymorphisms (SNPs) affecting obesity risk should smhooudludlamteotdruanlastceritpratinosncroifpgtieonneos fpgreefneersenptrieaflelyreenxtpiarlelysseexdpirneassdeidpoinseatdisispuoes,esthisosuuled,dshiroeuctlldy doivreercltalyp oevpeigrleanpeteipcigreegnueltaictorreygufelaattuorryesfesaeteunrepsresfeeernenptrieaflelyreinntiaadlliypoinseadtiispsuosee, atinsdsuseh, oaunldd sohvoeurlldapovaeTrlFaBpSathTaFtBiSs tbhoautnisdbtoouintsdTtFo istesleTcFtisveelleyctbivyeolynlbyyoonnelyofontheeotfwthoeatlwleoleas.llWeleesu
We showed that identifying credible candidates for obesity-risk regulatory SNPs using their subcutaneous adipose tissue (SAT) epigenetics and the expression in SAT and visceral adipose tissue (VAT) of their associated genes usually prioritized genes preferentially expressed in VAT as well as in SAT
Summary
The rapidly rising rates of obesity are a major concern for public health and increased risk of disease, including type 2 diabetes (T2D), cardiovascular disease, osteoarthritis, certain kinds of cancer, and respiratory problems [1,2]. Overall obesity, and the location of the fat depot with increased adipose tissue is of importance to health risk [2]. The major types of fat depots are visceral adipose tissue (VAT), which is deposited around internal organs in the abdominal cavity, and subcutaneous adipose tissue (SAT), which is beneath the skin. Adipose deposition around the hips, which mostly involves SAT, is less likely to be a risk factor for various chronic diseases than are high levels of adipose at the waist, which have a large VAT component. Pre-menopausal women with their tendency for high SAT/VAT ratios are at lower risk of adipose-related disease [4]
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