Tissue-specific multiOMICs analysis of atrial fibrillation

RATIONALE: Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. The molecular mechanisms of genotype-phenotype relationships, especially consequences of sequence variants for mRNA and protein expression remain largely elusive. Novel multiOMICs approaches are needed for deciphering the underlying molecular networks. Recently, an omnigenic model postulated the existence of core genes, that accumulate trans regulatory effects and are directly linked to disease phenotypes. However, the existence and identity of AF-relevant core genes remain unknown. OBJECTIVE: The aim was to systematically assess regulatory genetic variants and their downstream consequences on transcriptome, proteome and the disease phenotype AF on a genome-wide scale. METHODS AND RESULTS: We integrated genomics, transcriptomics, and proteomics of human atrial tissue. We identified widespread effects of genetic variants on transcript (cis eQTL) and protein (cis pQTL) abundance of nearby genes with an overrepresentation of GWAS variants for AF. To investigate more complex genetic mechanisms we established a novel approach to identify candidates for AF core genes, as postulated by the omnigenic model. Our approach combined a polygenic risk score for AF with pathway enrichment analysis to uncover biological processes related to the genetic susceptibility of AF. Within these biological processes, we identified two trans eQTLs and six trans pQTLs for AF GWAS hits involved in cardiac contractile function or metabolism. Furthermore, we elucidated the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and thirteen putative AF core genes with a consistent downregulation in AF on proteomics level. CONCLUSIONS: We established an integrative multiOMICs approach for the identification of AF core gene candidates and applied this technique to uncover trans-acting genetic networks in AF. We provide a valuable resource to investigate atrial tissue-specific regulatory variants for transcript and protein levels in the context of cardiovascular disease.