Bioinformatic and mendelian randomization analyses characterize variants in desmosomal genes associated with ECG traits in the general population
Del Greco M F
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Introduction: Arrhythmogenic cardiomyopathy is caused by mutations in desmosomal genes. We previously tested association of common variants in such genes with physiological cardiac conduction traits. From an analysis of 4342 subjects from the Cooperative Health Research In South Tyrol study, we reported association of two Junction Plakoglobin (JUP) SNPs with P wave length and one Desmoplakin (DSP) SNP with QRS interval. Material and Methods: In this subsequent study, we assessed replication in the MICROS (N=636), an independent study from the same geographical region, and in the Northern Germany SHIP/SHIP Trend (N=3797) studies. We characterized the variants and their genomic context using the SCREEN/ENCODE tool, the GTeX and methylation QTL (meQTL) databases, and Framingham Heart Study meQTL data (N=4170). We tested few biological hypotheses using two-sample Mendelian randomization (MR) based on Wald estimator, with standard errors computed via delta method. Results: The DSP rs2744389-QRS association was replicated in MICROS (p=0.010) but not in SHIP/SHIP Trend (p=0.505), suggesting genetic heterogeneity. We did not replicate the P wave associations. Falling in the DSP promoter, the rs2744389 is an eQTL of the antisense RNA RP3-512B11.3, and a meQTL of cg02643433. MR analysis showed evidence of a causal effect of cg02643433 methylation on QRS (p=0.001), of RP3-512B11.3 expression on QRS (p=0.030), but lacking evidence of a causal effect of RP3-512B11.3 expression on cg02643433 methylation (p=0.090). Conclusions: While needing to understand the reasons for the partial lack of replication, MR results suggest an antisense RNA-mediated mechanism of DSP expression control to be validated with laboratory experiments.