Allele-specific expression analysis for complex genetic phenotypes applied to a unique dilated cardiomyopathy cohort

Abstract

Allele-specific expression (ASE) analysis detects the relative abundance of alleles at heterozygous loci as a proxy for cis-regulatory variation, which affects the personal transcriptome and proteome. This study describes the development and application of an ASE analysis pipeline on a unique cohort of 87 well phenotyped and RNA sequenced patients from the Maastricht Cardiomyopathy Registry with dilated cardiomyopathy (DCM), a complex genetic disorder with a remaining gap in explained heritability. Regulatory processes for which ASE is a proxy might explain this gap. We found an overrepresentation of known DCM-associated genes among the significant results across the cohort. In addition, we were able to find genes of interest that have not been associated with DCM through conventional methods such as genome-wide association or differential gene expression studies. The pipeline offers RNA sequencing data processing, individual and population level ASE analyses as well as group comparisons and several intuitive visualizations such as Manhattan plots and protein–protein interaction networks. With this pipeline, we found evidence supporting the case that cis-regulatory variation contributes to the phenotypic heterogeneity of DCM. Additionally, our results highlight that ASE analysis offers an additional layer to conventional genomic and transcriptomic analyses for candidate gene identification and biological insight.

Sexual antagonism and sex determination in three syngnathid species alongside a male pregnancy gradient

“…ASE can arise from chromosome inactivation, regulatory elements, nonsense-mediated decay, or imprinting (Castel et al 2015; Fan et al 2020). While extensively studied in human pathology (Langmyhr et al 2021; Rao et al 2021; Van Beek et al 2023), sex-specific ASE in the context of SA selection remains underexplored.…”

Differential expression analyses on aortic tissue reveal novel genes and pathways associated with abdominal aortic aneurysm onset and progression

“…We used the allele specific expression data obtained by the GTEx consortium to compare allele specific expression between our AAA samples and GTEx control tissues [78]. To do this, we compared the proportional expression of each allele between our AAA samples and the GTEx controls, using a non-parametric Wilcoxon test [79]. Then, to identify genes with distinct allele specific expression patterns, we corrected for multiple comparisons using FDR [67].…”

Transcriptomics and Beyond in Dilated Cardiomyopathy

“…Allele-specific expression analyses should also help to assess the role of cis-regulatory events such as differential messenger RNA splicing, nonsense-mediated decay, X-inactivation, locus imprinting, or RNA interference in DCM. 5 …”