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.