Tissue-specific multi-omics analysis of atrial fibrillation

Area of Science:

• Cardiovascular Genetics
• Molecular Biology
• Systems Biology

Background:

• Genome-wide association studies (GWAS) have identified numerous variants linked to atrial fibrillation (AF).
• The molecular mechanisms, particularly effects on mRNA and protein expression, remain largely unknown.
• Advanced multi-omics approaches are crucial for understanding AF-related molecular networks.

Purpose of the Study:

• To integrate genomics, transcriptomics, and proteomics in human atrial tissue.
• To identify cis-acting regulatory variants affecting transcript (cis-eQTL) and protein (cis-pQTL) abundance.
• To develop a targeted trans-quantitative trait loci (trans-QTL) approach for discovering AF core genes.

Main Methods:

• Cross-sectional study integrating multi-omics data from human atrial tissue.
• Identification of cis-eQTLs and cis-pQTLs.
• Application of a novel polygenic risk score-based targeted trans-QTL analysis.

Main Results:

• Widespread effects of genetic variants on transcript and protein levels were identified.
• Two trans-eQTLs and five trans-pQTLs associated with AF GWAS hits were discovered.
• The transcription factor NKX2-5 was identified as a key link between a specific GWAS SNP (rs9481842) and AF.

Conclusions:

• An integrative multi-omics method was developed to uncover trans-acting networks, even in small datasets.
• This study provides a valuable resource of atrial tissue-specific regulatory variants for cardiovascular disease gene prioritization.
• The findings offer new insights into the molecular basis of AF and potential therapeutic targets.