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

Area of Science:

• Genetics
• Epigenetics
• Molecular Biology

Background:

• Rising obesity rates necessitate identification of genetic factors contributing to the condition.
• Genome-wide association studies (GWAS) have identified numerous obesity-related single nucleotide polymorphisms (SNPs), but pinpointing causal regulatory SNPs is challenging due to linkage disequilibrium.

Purpose of the Study:

• To identify and prioritize potential causal regulatory SNPs associated with obesity using an integrated epigenomic and transcriptomic approach.
• To evaluate the regulatory potential of previously identified obesity GWAS SNPs.

Main Methods:

• Analysis of epigenomic and transcriptomic data from adipose and other tissues.
• Prioritization of SNPs from 50 GWAS and 121,064 expanded SNPs to identify potential causal regulatory SNPs (Tier-1 SNPs).
• Detailed examination of seven gene loci with Tier-1 SNPs to assess their regulatory mechanisms.

Main Results:

• Forty-seven Tier-1 SNPs were prioritized for 14 gene loci.
• Four loci (CABLES1, PC, PEMT, FAM13A) showed Tier-1 SNPs regulating alternative transcription start sites or intronic microRNA expression.
• HOXA11 and RP11-392O17.1 exhibited tissue-specific expression preferences influenced by Tier-1 SNPs.
• ZBED3-AS1 had intragenic Tier-1 SNPs potentially mediating obesity risk through chromatin interactions.

Conclusions:

• The study successfully identified credible novel regulatory SNPs associated with obesity.
• The integrated approach aids in evaluating the functional relevance of GWAS-identified SNPs in obesity pathogenesis.
• Findings provide insights into molecular mechanisms underlying obesity risk conferred by specific genetic variants.