New Study Reveals Rare Genetic Variants Significantly Increase Atrial Fibrillation Risk

In a recent study published in the journal JAMA Cardiology, a group of researchers identified rare predicted loss-of-function variants associated with atrial fibrillation (AF) and elucidated their role in the risk of AF, cardiomyopathy, and heart failure (HF) in combination with a polygenic risk score (PRS).

Study: Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk. Image Credit: hywards / Shutterstock

Background

AF is the most common cardiac arrhythmia linked to increased risks of stroke, HF, and premature death. While genome-wide association studies (GWAS) have identified common genetic variants linked to AF, accurately pinpointing the specific causal genes remains a significant challenge. Rare coding variants, however, often have large effect sizes on disease risk and prognosis, which may be clinically significant. Recent studies suggest genetic testing for certain AF subpopulations. Further research is needed to better understand the genetic underpinnings of AF, particularly the impact of rare variants, to enhance risk stratification and develop targeted therapies.

About the study

The present study was conducted in the United Kingdom (UK) Biobank and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Participants provided informed consent, and ethical approval was obtained. The UK Biobank includes genetic and clinical data on nearly 500,000 individuals. Rare coding variants were analyzed using gene-based burden tests, focusing on rare predicted loss-of-function (pLOF) variants across 17,979 genes. Secondary tests for rare missense variants were also conducted.

Variants with minor allele frequencies under 1% were included, excluding gene masks with cumulative allele counts below 10. Associations were tested using genome-wide regression, adjusting for age, sex, and principal components, with significance set at  P < 2.77 × 10⁻⁶. Sensitivity analyses and replication in external datasets ensured robustness. Protein and Ribonucleic Acid (RNA) expression were evaluated for genes with significant pLOF variants.

PRS was calculated for the impact of common genetic variation, normalized to a mean of 0 with a standard deviation (SD) of 1. Odds ratios (OR) for AF were derived from logistic regression models. Incident AF, cardiomyopathy, and HF risks were assessed using Cox regression models, adjusted for clinical risk factors, with follow-up until AF diagnosis, death, or the end of the study. 

Study results 

The study conducted gene-based association tests across the exome of 403,990 individuals. Baseline characteristics indicated a median age of 58, with 54.1% female participants. A total of 31,124 individuals with AF were defined as cases, while 372,871 served as controls. Significant associations between AF and pLOF variants were found in Plakophilin 2 (PKP2), Catenin Alpha 3 (CTNNA3), Chromosome 10 Open Reading Frame 71 (C10orf71), Lysine Demethylase 5B

(KDM5B), Titin (TTN), and Ribosomal Protein L3 (RPL3L) genes. The associations for TTN and RPL3L were previously reported. These findings were replicated in an external cohort of 17,910 individuals with AF and 149,348 controls. Protein and RNA expression analyses showed that most associated genes were predominantly expressed in cardiomyocytes.

Secondary analyses focused on pLOF variants in TTN cardiac isoforms and constitutively expressed exons, revealing an even greater OR for AF. Additionally, secondary gene-based tests for rare missense variants identified an association with Ubiquitination Factor E4B (UBE4B). Sensitivity analyses confirmed the robustness of the results, except for RPL3L and UBE4B. PRS analyses showed a significant OR for AF, with a combined PRS and pLOF variant model indicating a markedly increased OR for AF in high-risk groups. The combined OR for AF in high-risk groups was 7.08 (95% CI, 6.03-8.28).

Incident AF risk assessment excluded individuals with prevalent AF, HF, or cardiomyopathy at baseline. During a median follow-up of 13.3 years, 24,061 individuals were diagnosed with incident AF. Those with a high PRS and a rare pLOF variant had a significantly increased hazard ratio (HR) for incident AF compared to low-risk groups. Absolute risk analyses indicated a cumulative AF incidence of 28.55% by age 80 for high-risk individuals, compared to 8.1% for low-risk groups. Sensitivity analyses in unrelated individuals supported these findings.

Genetic predisposition to AF also influences the risk of HF and cardiomyopathy. Rare pLOF variants in AF-associated genes conferred increased HRs for incident AF, cardiomyopathy, and HF. Excluding TTN variants attenuated these effects, particularly for cardiomyopathy and HF. The AF PRS was significantly associated with AF but not with cardiomyopathy or HF. In individuals diagnosed with AF post-inclusion, rare pLOF variants were linked to an increased HR for cardiomyopathy but not when excluding TTN variants or considering the PRS. In another subgroup with incident cardiomyopathy or HF, no significant associations were found between pLOF variants or the PRS and incident AF. Sensitivity analyses and application of a 30-day grace period did not substantially alter the results.

Conclusions

To summarize, in this genetic association study, researchers analyzed whole-exome sequencing data from over 400,000 UK Biobank participants, including 31,000 with AF. They identified rare pLOF variants in several genes, significantly increasing AF risk. Combining PRSs with these rare variants further elevated the risk of incident AF. Novel associations were found with CTNNA3 and KDM5B, while confirming links to TTN and PKP2. The findings suggest that including both common and rare genetic variations can enhance AF risk stratification, supporting genetic testing in specific patient groups, particularly those with early-onset AF.