Epigenomic and Transcriptomic Prioritization of Candidate Obesity-Risk Regulatory GWAS SNPs

• Published in: International journal of molecular sciences 2022-01, Vol.23 (3), p.1271
• Main Authors: Zhang, Xiao, Li, Tian-Ying, Xiao, Hong-Mei, Ehrlich, Kenneth C, Shen, Hui, Deng, Hong-Wen, Ehrlich, Melanie
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipose tissue; Binding sites; Body fat; Body mass index; Candidates; Chromatin; Chromatin - genetics; Computational Biology - methods; Disease; Epigenesis, Genetic - genetics; Epigenetics; Epigenomics - methods; Gene Expression - genetics; Gene Expression Profiling - methods; Gene Expression Regulation - genetics; Gene loci; Gene regulation; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; GWAS; Health risk assessment; Humans; Linkage disequilibrium; Linkage Disequilibrium - genetics; lncRNA; miRNA; Nucleotides; Obesity; Obesity - genetics; Obesity - metabolism; Polymorphism, Single Nucleotide - genetics; Polypeptides; Quantitative Trait Loci - genetics; RNA isoforms; Single-nucleotide polymorphism; SNPs; Statistical methods; Transcription; Transcription factors; Transcription Factors - metabolism; Transcriptome - genetics; Transcriptomics
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031271

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 ( , , , and ) 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. and long noncoding RNA gene had Tier-1 SNPs in their 3' or promoter region, respectively, and strong preferences for expression in subcutaneous versus visceral adipose tissue. 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.