Tissue-specific multi-omics analysis of atrial fibrillation.

Abstract

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.

• Authors: Ines Assum, Julia Krause, Markus O Scheinhardt, Christian Müller, Elke Hammer, Christin S Börschel, Uwe Völker, Lenard Conradi, Bastiaan Geelhoed, Tanja Zeller, Renate B Schnabel, Matthias Heinig
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 441 (01 21 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35064145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Homeobox Protein Nkx-2.5
• NKX2-5 protein, human

Topics

• Atrial Fibrillation (genetics)
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Genomics
• Homeobox Protein Nkx-2.5 (genetics, metabolism)
• Humans
• Organ Specificity
• Polymorphism, Single Nucleotide (genetics)
• Quantitative Trait Loci (genetics)