After a long journey, we could finally publish this fantastic work.
The reseach, led by outstanding Luisa Foco, started from the interest of our colleagues Alessandra Rossini and Marzia De Bortoli into the molecular mechanisms of arrhythmogenic cardiomyopathy. We observed that most disease-causing mutations occur in desmosomal genes. Given rare inherited and common chronic conditions are at different ends of a common genetic background, we conducted genomic association studies between common variants at the 5 desmosomal genes and ECG traits assessed in general population individuals. Our key finding was a variant located in the DSP gene associated with the QRS interval.
Functional annotation revealed that the variant is located in a short segment where the DSP gene overlaps one of its antisense microRNA, the DSP-AS1. Interestingly, the identified variant was associated with DSP-AS1 but not DSP expression. Two-sample Mendelian randomization revealed a causal effect of the antisense RNA DSP-AS1 on both DSP and QRS interval. The causal effect of DSP-AS1 on DSP was confirmed by in vitro experiments on human induced pluripotent stem cell derived cardiomyocytes. Altogether, these findings support DSP-AS1 as a potential target for DSP-related diseases.