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.

RETRACTED: The effect of ischemia on expression quantitative trait loci (eQTL) in human myocardium and insights into myocardial injury etiology

“…Due to the cis effect of single nucleotide polymorphism (SNP) alleles on transcription and translation gene expression quantitative trait loci (eQTL), some eQTL are disease-context dependent, observable only under speci c physiological conditions, e.g., unique stress or stimulus. eQTL shows a high degree of tissue speci city [8][9][10] , emphasizing the need to examine disease organ tissue. Therefore, we studied patients experiencing myocardial ischemia while undergoing cardiac surgery with cardiopulmonary bypass (CPB).…”

CDK5R1, GSE1, HSPG2 and WDFY3 as indirect epigenetic‐sensitive genes in atrial fibrillation

“…[22][23][24][25][26]28,29 Specifically, AF multiomic analysis on atrial tissues has provided novel into the molecular pathways implicated in the pathology. 4,32,50,51 However, the need of cardiac biopsies, has limited enthusiasm of this technology to a small subpopulation of AF including those with valvular heart disease or CHD, for whom surgical intervention is already warranted. To overcome this, a surrogate tissue source is warranted to provide an indirect epigenetic and/or transcriptional phenotyping to mirror the failing myocardium.…”

“…A mounting body of evidence supports a future for ‘clinical epigenetics’ in cardiovascular medicine 22–26,28,29 . Specifically, AF multiomic analysis on atrial tissues has provided novel insights into the molecular pathways implicated in the pathology 4,32,50,51 . However, the need of cardiac biopsies, has limited enthusiasm of this technology to a small subpopulation of AF patients including those with valvular heart disease or CHD, for whom surgical intervention is already warranted.…”

Integration of Candida albicans-induced single-cell gene expression data and secretory protein concentrations reveal genetic regulators of inflammation

“…However, which specific cell type is contributing to the production of these secretory proteins is unclear. In addition, by examining the relationship between pQTLs and eQTLs, previous studies have demonstrated the disparity of genetic variants associated with mRNA expressions and protein abundances as summarized by a minireview ( 7 ), and a recently published study affirms this observation with substantial difference between pQTLs and eQTLs where only 32% of the index eQTLs variants were replicated in pQTLs ( 8 ). While previous studies examining the extent of overlap between pQTLs and eQTLs extensively explored steady-state conditions, the degree to which these findings are replicated in stimulated conditions remain elusive.…”