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.
In this truly interdisciplinary (biology, bioinformatics, medicine, epidemiology) study scientists from the DZHK partner sites Munich, Hamburg, Lübeck and Greifswald performed a multi-omics approach and integrated genomics, transcriptomics, and proteomics of human atrial tissue in a cross-sectional study. They evaluated effects of genetic variants on both transcript (cis-eQTL) and protein (cis-pQTL) abundance. By establishing a novel „targeted trans-QTL“ approach guided by a polygenic risk score model, two novel trans-eQTLs and five trans-pQTLs for AF GWAS hits were identified. In particular, the transcription factor NKX2-5 was proposed as a link between a genetic variant and AF, suggesting NKX-2 as a strong candidate for molecular follow up analyses.
Taken together, the presented work of integrative multi-omics methods permits the identification of shared and independent effects of cis-acting variants on transcript expression and protein abundance and makes trans-QTL analyses feasible even in small datasets. A rich resource of atrial tissue-specific regulatory variants for transcript and protein levels for cardiovascular disease gene prioritization is provided in an interactive browser. This study also demonstrates the success of highly efficient interdisciplinary translational research across DZHK study sites.