Abstract
Purpose
Arrhythmogenic cardiomyopathy (AC) is a rare condition, with familial inheritance, featuring life-threatening arrhythmias and cardiomyocite replacement with fibro-fatty cells. Such alterations are reflected in both depolarization and repolarization abnormalities at the electrocardiogram (ECG) level.
Mutations in genes encoding cardiac desmosomal proteins are an established cause of AC. Given that common genetic architecture is often observed between Mendelian diseases and related complex traits, we hypothesised that common variants in desmosomal genes, involved in the electrical coupling between cardiomyocytes, could influence the cardiac conduction traits in the general population.
Methods
Through linkage-disequilibrium analysis of SNPs from the HumanOmniExpressExome Bead Chip imputed using 1000 Genome panel Phase 3, we selected 2429 SNPs in the desmosomal genes Desmoplakin (DSP), Plakophilin 2 (PKP2), Desmoglein 2 (DGS2), Desmocollin 2 (DSC2), and Junction Plakoglobin (JUP). SNPs were tested for association with P wave, PR, QRS, and QT intervals, derived from 10 sec ECGs, in 4979 participants to the Cooperative Health Research in South Tyrol (CHRIS) study. We fitted age- and sex- adjusted linear mixed models accounting for population relatedness and assuming additive genetic effects. Multiple testing corrected significance was set at 1.9x10-4 based on the percentage of genome covered by the tested regions.
Results
Two independent SNPs, rs115171396 (MAF=0.02) and rs72835665 (MAF=0.49) in JUP, were associated with P wave length, with effects of 4.87 (SE=1.08, P-value=6.6*10-6) and -1.10 (SE=0.27, P-value=4.5*10-5) milliseconds (ms) per copy of the minor allele, respectively. Variant rs2744389 in DSP was associated with QRS duration: effect= -1.10 ms (SE=0.24, P-value=3.5*10-6). We did not find evidence of association with PR interval and QT duration.
Conclusions
While awaiting independent replication, the results suggest that variants in desmosomal genes could impact the cardiac electric function in the general population. Ongoing whole exome sequencing analyses will allow finer mapping of the investigated genes.