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Brugada Syndrome GWAS Reveals Role of Sodium Channel, Other Contributors to Heart Condition

NEW YORK – A large international team has teased out a dozen genetic loci with ties to Brugada syndrome, a cardiac arrhythmia condition that has been linked to sudden death risk in young adults.

"Taken together, these findings broaden our understanding of the genetic architecture of [Brugada syndrome] and provide new insights into its molecular underpinnings," co-corresponding and co-senior author Connie Bezzina, a clinical and experimental cardiology researcher affiliated with the University of Amsterdam and the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart, and her colleagues wrote in Nature Genetics on Thursday.

With a genome-wide association study meta-analysis that encompassed 2,820 individuals of European ancestry with Brugada syndrome and more than 10,000 unaffected control individuals, the researchers narrowed in on 21 variants with ties to the heart condition, including signals at two new loci and 10 loci implicated in the condition in previous studies.

Together with a transcriptome-wide analysis based on cardiac gene expression, their analyses highlighted at least 18 genes showing apparent ties to Brugada syndrome in both the GWAS and TWAS arms of the study.

Along with several variants falling in sodium channel isoform-coding genes such as SCN5A — which has been implicated in the cardiac condition in the past through rare and common variant analyses — the team's gene set enrichment analyses pointed to the apparent importance of genes and pathways related to heart development, heart growth, and transcriptional regulation.

"These data support the concept that disease susceptibility in different individuals relies upon varying contributions of multiple factors, including both rare and common genetic variations and exposure to sodium channel blockade," they wrote.

With a polygenic risk score, or PRS, comprised of new and known Brugada syndrome-associated variants, the team performed a phenome-wide association study using data from the UK Biobank study, demonstrating that the genetic risk score was particularly tied to heart features such as atrioventricular conduction. On the other hand, the Brugada syndrome PRS was negatively associated with other cardiac traits or conditions, including QT interval duration and atrial fibrillation.

Meanwhile, at least one Brugada syndrome-related variant in and around the MAPRE2 gene appeared to influence the expression of that microtubule binding protein-coding gene, prompting a series of zebrafish or human cell line gene editing, optical mapping, and other functional experiments suggesting potential interactions between microtubule-dependent transport and the expression of the SCN5A cardiac sodium channel.

When they considered the PRS in relation to rare alterations in SCN5A in 2,469 individuals with Brugada syndrome, the authors saw signs that the 454 patients with rare pathogenic or likely pathogenic mutations in the sodium channel gene tended to have lower-than-usual polygenic risk than individuals without rare SCN5A mutations.

Together, the authors noted that their PRS analyses "support the concept that disease threshold in different individuals with [Brugada syndrome] is reached by varying contribution of rare SCN5A variants, common risk alleles, and sodium channel blockade."