Genomic and molecular evidence that the lncRNADSP-AS1modulates Desmoplakin expression
Abstract
Cardiac desmosomes are specialized cell junctions responsible for cardiomyocytes mechanical coupling. Mutation in desmosomal genes cause autosomal dominant and recessive familial arrhythmogenic cardiomyopathy. Motivated by evidence that Mendelian diseases share genetic architecture with common complex traits, we assessed whether common variants in any desmosomal gene were associated with cardiac conduction traits in the general population.
We analysed data of N=4342 Cooperative Health Research in South Tyrol (CHRIS) study participants. We tested associations between genotype imputed variants covering the five desmosomal genesDSP, JUP, PKP2, DSG2,andDSC2, and P-wave, PR, QRS, and QT electrocardiographic intervals, using linear mixed models. Functional annotation and interrogation of publicly available genome-wide association study resources implicated potential connection with antisense lncRNAs, DNA methylation sites, and complex traits. Causality was tested via two-sample Mendelian randomization (MR) analysis and validated with functionalin vitrofollow-up in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs).
DSPvariant rs2744389 was associated with QRS (P=3.5×10-6), with replication in the Microisolates in South Tyrol (MICROS) study (n=636;P=0.010). Observing that rs2744389 was associated withDSP-AS1antisense lncRNA but not withDSPexpression in multiple GTEx-v8 tissues, we conducted two-sample Mendelian randomization analyses that identified causal effects ofDSP-AS1onDSPexpression (P=6.33×10-5; colocalization posterior probability=0.91) and QRS (P=0.015). In hiPSC-CMs,DSP-AS1expression downregulation through a specific GapmerR matching sequence led to significantDSPupregulation at both mRNA and protein levels.
The evidence thatDSP-AS1has a regulatory role onDSPopens the venue for further investigations onDSP- AS1’s therapeutic potential for conditions caused by reduced desmoplakin production.
Author Summary
Arrhythmogenic Cardiomyopathy is a severe condition mainly caused by pathogenic variants in genes encoding components of the cardiac desmosome, a specialised cell junction.
Given complex traits and Mendelian diseases share common genetic background, we hypothesised that common variants in any of the five desmosomal genes (DSP, JUP, PKP2, DSG2,andDSC2) could be associated with electrocardiographic measurements in general population individuals.
Analyzing data from >4000 participants from the Cooperative Research In South Tyrol (CHRIS) study, we identified an association between a variant in the desmoplakin gene (DSP) and QRS, which represents the time needed for ventricular electrical activation.
Downstream gene expression analyses showed that the identified variant was not associated with the expression ofDSPbut with that of an uncharacterized long non-coding antisense RNA,DSP-AS1.
Mendelian randomization (MR) analyses, performed leveraging publicly available data, supported a causal effect ofDSP-AS1expression onDSPexpression.
In vitrofunctional follow-up showed that silencingDSP-AS1inducesDSPtranscript and desmoplakin protein upregulation, suggesting thatDSP-AS1is involved in the regulation ofDSPexpression and validating MR findings.
Our study represents a first step in the functional characterization ofDSP-AS1, a potential target for treatment of diseases caused by low amounts of desmoplakin.
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