Genome-wide association studies (GWAS) for atrial fibrillation (AF) have uncovered numerous disease-associated variants. Their underlying molecular mechanisms, especially consequences for mRNA and protein expression remain largely elusive. Thus, refined multi-omics approaches are needed for deciphering the underlying molecular networks. Here, we integrate genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study to identify widespread effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. We further establish a novel targeted trans-QTL approach based on polygenic risk scores to determine candidates for AF core genes. Using this approach, we identify two trans-eQTLs and five trans-pQTLs for AF GWAS hits, and elucidate the role of the transcription factor NKX2-5 as a link between the GWAS SNP rs9481842 and AF. Altogether, we present an integrative multi-omics method to uncover trans-acting networks in small datasets and provide a rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization.
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 e ects 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 e ects 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.Tissue-specific multiOMICs analysis of atrial fibrillation April 6, 2020 heart coronary bypass surgery. For the current analyses, N=118 patients with multiOMICs data were available. Cardiovascular risk factor information was collected by questionnaire and from medical records. Baseline blood samples were aliquoted and stored prior to surgery. Atrial appendage tissue remnants were collected when the extracorporeal circulation was started and shock frozen immediately. Follow-up for AF and other cardiovascular disease outcomes was by questionnaire and medical chart review. The observational cohort study was approved by Ethikkommission Ärztekammer Hamburg (PV3982). The study was performed in compliance with the Declaration of Helsinki. The study enrollment and follow-up procedures were in accordance with institutional guidelines. All participants provided written informed consent. Sex stratification of the results was not possible due ...
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