Rare-variant collapsing and bioinformatic analyses for different types of cardiac arrhythmias in the UK Biobank reveal novel susceptibility loci and candidate amyloid-forming proteins.

BACKGROUND: Cardiac arrhythmias are a common health problem. Both common and rare genetic risk factors exist for cardiac arrhythmias. Cardiac amyloidosis is a rare disease that may manifest various arrhythmias. Few large-scale whole exome sequencing studies elucidating the contribution of rare variations to arrhythmias have been published.

OBJECTIVE: To access gene collapsing analysis of rare variations for different types of cardiac arrhythmias in UK Biobank. Identified genes were analyzed in silico for probability to form amyloid fibrils.

METHODS: We used 2 published UK Biobank portals (https://azphewas.com/ and https://app.genebass.org/) to access gene collapsing analysis of rare variations for different types of cardiac arrhythmias. Diagnosis of arrhythmia was based on the International Classification of Diseases, 10th Revision (ICD-10) codes: conduction disorders (I44, I45), paroxysmal tachycardia (I47), atrial fibrillation (I48), and other arrhythmias (I49).

RESULTS: Rare variations in 5 genes were linked to conduction disorders ( SCN5A, LMNA , SMAD6 , HSPB9, TMEM95 ). The TTN gene was associated with both paroxysmal tachycardia and other arrhythmias. Atrial fibrillation was associated with rare variations in 8 genes ( TTN , RPL3L, KLF1, TET2, NME3, KDM5B, PKP2, PMVK ). Two of the genes linked to heart conduction disorders were potential amyloid-forming proteins ( HSPB9, TMEM95 ), while none of the 8 genes linked to other types of arrhythmias were potential amyloid-forming proteins.

CONCLUSION: Rare variations in 13 genes were associated with arrhythmias in the UK Biobank. Two of the heart conduction disorder-linked genes are potential amyloid-forming candidates. Amyloid formation may be an underestimated cause of heart conduction disorders.