Tissue-specific multi-omics analysis of atrial fibrillation

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 () and Matthias Heinig ()
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Ines Assum: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Julia Krause: University Heart and Vascular Center Hamburg
Markus O. Scheinhardt: University of Lübeck, University Hospital of Schleswig-Holstein
Christian Müller: University Heart and Vascular Center Hamburg
Elke Hammer: University Medicine Greifswald
Christin S. Börschel: DZHK (German Center for Cardiovascular Research)
Uwe Völker: University Medicine Greifswald
Lenard Conradi: University Heart and Vascular Center Hamburg
Bastiaan Geelhoed: DZHK (German Center for Cardiovascular Research)
Tanja Zeller: University Heart and Vascular Center Hamburg
Renate B. Schnabel: DZHK (German Center for Cardiovascular Research)
Matthias Heinig: Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-27953-1

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