RESUMEN
Genetic studies suggest that hundreds of genes associated with stroke remain unidentified. Exome sequencing proves useful for finding new genes associated with stroke. We aimed to find new genetic risk factors for cardioembolic stroke by analysing exome sequence data using new strategies. For discovery, we analysed 42 cardioembolic stroke cases and controls with extreme phenotypes (cohort 1), and for replication, 32 cardioembolic stroke cases and controls (cohort 2) using the SeqCapExome capture kit. We then analysed the replicated genes in two new cohorts that comprised 834 cardioembolic strokes and controls (cohort 3) and 64,373 cardioembolic strokes and controls (cohort 4). Transcriptomic in-silico functional analyses were also performed. We found 26 coding regions with a higher frequency of mutations in cardioembolic strokes after correcting for the number of mutations found in the whole exome of every patient. The TRPV3 gene was associated with cardioembolic stroke after replication of exome sequencing analysis (p-value-discovery: 0.018, p-value-replication: 0.014). The analysis of the TRPV3 gene using polymorphisms in cohort 3 and 4 revealed two polymorphisms associated with cardioembolic stroke in both cohorts, the most significant polymorphism being rs151091899 (p-value: 3.1 × 10-05; odds ratio: 5.4) in cohort 3. The genotype of one polymorphism of TRPV3 was associated with a differential expression of genes linked to cardiac malformations. In conclusion, new strategies using exome sequence data have revealed TRPV3 as a new gene associated with cardioembolic stroke. This strategy among others might be useful in finding new genes associated with complex genetic diseases.