Systematic functional characterization of non-coding regulatory SNPs associated with central obesity.

Area of Science:

• Genetics
• Metabolic Diseases
• Epigenetics

Background:

• Central obesity is a risk factor for various diseases, independent of overall body fat.
• Genome-wide association studies (GWASs) have identified numerous genetic loci linked to central obesity, but their functional roles remain unclear, especially for non-coding regions.

Purpose of the Study:

• To functionally characterize genetic loci associated with central obesity.
• To identify regulatory elements and transcription factors mediating central obesity risk.
• To elucidate the molecular mechanism of specific genetic variants in regulating gene expression related to obesity.

Main Methods:

• Prioritization of 2,034 single-nucleotide polymorphisms (SNPs) using fine-mapping and epigenomic data.
• Systematic evaluation of enhancer activity for prioritized SNPs using self-transcribing active regulatory region sequencing (STARR-seq).
• Analysis of allelic transcription factor (TF) binding to identify key regulatory factors.

Main Results:

• Identified 141 SNPs exhibiting allelic enhancer activity.
• Prioritized 20 key transcription factors involved in the central obesity genetic regulatory network.
• Demonstrated the allele-specific enhancer function of rs8079062 in regulating RNF157 expression and its role in adipogenesis.

Conclusions:

• The study provides a valuable resource for understanding the genetic and regulatory mechanisms of central obesity.
• Identified novel functional SNPs and TFs contributing to central obesity.
• Elucidated a specific molecular mechanism involving rs8079062 and RNF157 in adipogenesis.