BS-513-02 GENOME-WIDE ASSOCIATION ANALYSES IDENTIFY NOVEL BRUGADA SYNDROME RISK LOCI AND HIGHLIGHT A NEW MECHANISM OF SODIUM CHANNEL REGULATION IN DISEASE SUSCEPTIBILITY

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel NaV1.5, susceptibility genes remain largely unknown.

Evaluate the contribution of the common variants in the genetic architecture of the BrS.

We performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls.

We identified 21 association signals (18 novel) at 12 loci (10 novel). Seven association signals overlap SCN5A and one overlaps the neighboring SCN10A gene encoding the sodium channel isoform NaV1.8 highlighting the primacy of sodium channel function in BrS susceptibility. Notably, 10 association signals overlapped or are in the vicinity of 8 genes encoding cardiac developmental transcription factors (HEY2, TBX20, ZFPM2, GATA4, WT1, TBX5, IRX3 and IRX5) pointing to transcriptional regulation as a key feature of BrS pathogenesis. One additional association signal overlapped PRKCA, involved in contractility and calcium handling in cardiomyocytes and two other overlapped genes encoding myofiber or microtubule associated proteins, namely MYO18B and MAPRE2. Functional studies of MAPRE2 support a novel mechanism of NaV1.5 modulation. We calculated a polygenic risk score (PRS_BrS) per individual based on the 21 risk alleles, which was higher in SCN5A negative BrS patients compared to SCN5A positive as well as in cases with a spontaneous type 1 BrS ECG compared to those diagnosed after sodium blockers challenge and particularly in SCN5A negative patients. Based on the PRS_BrS, we performed a phenome-wide association study in the UK Biobank. PRS_BrS was associated with greater risk for atrioventricular conduction disorders, a longer ECG activation/conduction times reflected in the P-wave duration, PQ interval duration and QRS duration. In contrast, PRS_BrS was negatively associated with the QT interval duration and with the occurrence of atrial fibrillation or flutter.

Taken together, these findings broaden our understanding of the genetic architecture of Brugada syndrome and provide new insights into its molecular underpinnings.