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. 2024 Aug 1;9(8):732-740.
doi: 10.1001/jamacardio.2024.1528.

Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk

Oliver B Vad  1   2 , Laia M Monfort  1   2 , Christian Paludan-Müller  1   2 , Konstantin Kahnert  2 , Søren Z Diederichsen  1 , Laura Andreasen  1   2 , Luca A Lotta  3 , Jonas B Nielsen  3 , Alicia Lundby  2 , Jesper H Svendsen  1   4 , Morten S Olesen  1   2 ; Geisinger MyCode Community Health Initiative and the Regeneron Genetics Center (RGC) Research Team
Collaborators, Affiliations

Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk

Oliver B Vad et al. JAMA Cardiol. .

Abstract

Importance: Atrial fibrillation (AF) has a substantial genetic component. The importance of polygenic risk is well established, while the contribution of rare variants to disease risk warrants characterization in large cohorts.

Objective: To identify rare predicted loss-of-function (pLOF) variants associated with AF and elucidate their role in risk of AF, cardiomyopathy (CM), and heart failure (HF) in combination with a polygenic risk score (PRS).

Design, setting, and participants: This was a genetic association and nested case-control study. The impact of rare pLOF variants was evaluated on the risk of incident AF. HF and CM were assessed in cause-specific Cox regressions. End of follow-up was July 1, 2022. Data were analyzed from January to October 2023. The UK Biobank enrolled 502 480 individuals aged 40 to 69 years at inclusion in the United Kingdom between March 13, 2006, and October 1, 2010. UK residents of European ancestry were included. Individuals with prior diagnosis of AF were excluded from analyses of incident AF.

Exposures: Rare pLOF variants and an AF PRS.

Main outcomes and measures: Risk of AF and incident HF or CM prior to and subsequent to AF diagnosis.

Results: A total of 403 990 individuals (218 489 [54.1%] female) with a median (IQR) age of 58 (51-63) years were included; 24 447 were diagnosed with incident AF over a median (IQR) follow-up period of 13.3 (12.4-14.0) years. Rare pLOF variants in 6 genes (TTN, RPL3L, PKP2, CTNNA3, KDM5B, and C10orf71) were associated with AF. Of these, TTN, RPL3L, PKP2, CTNNA3, and KDM5B replicated in an external cohort. Combined with high PRS, rare pLOF variants conferred an odds ratio of 7.08 (95% CI, 6.03-8.28) for AF. Carriers with high PRS also had a substantial 10-year risk of AF (16% in female individuals and 24% in male individuals older than 60 years). Rare pLOF variants were associated with increased risk of CM both prior to AF (hazard ratio [HR], 3.13; 95% CI, 2.24-4.36) and subsequent to AF (HR, 2.98; 95% CI, 1.89-4.69).

Conclusions and relevance: Rare and common genetic variation were associated with an increased risk of AF. The findings provide insights into the genetic underpinnings of AF and may aid in future genetic risk stratification.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vad reported grants from Research Foundation at Rigshospitalet, the Department of Clinical Medicine, University of Copenhagen, and Skibsreder Per Henriksen, R, og hustrus fond during the conduct of the study. Dr Diederichsen reported personal fees from Bristol Myers Squibb, Pfizer, Bayer, Cortrium, and Acesion Pharma and grants from Abbott and Boston Scientific outside the submitted work. Dr Lotta reported other from Regeneron Pharmaceuticals (employment, stocks, and stock options) during the conduct of the study and outside the submitted work. Dr Nielsen reported other from Regeneron Pharmaceuticals (employment, stocks, and stock options) during the conduct of the study and outside the submitted work. Dr Lundby reported grants from Novo Nordisk during the conduct of the study. Dr Svendsen reported personal fees from Medtronic (speaker fee and member of advisory board) and Vital Beats (member of advisory board) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Risk of Atrial Fibrillation (AF) According to Polygenetic Risk Score (PRS) and Rare Variants
A, Odds ratios for AF in UK Biobank cohort are stratified by PRS quintile and carrier status of rare predicted loss-of-function (pLOF) variants in AF-associated genes. The group with a low PRS (0%-20%) and no pLOF variant is considered as the reference, with the base line representing the reference odds ratio of 1.0. B, Absolute risk of AF in shown by age, based on PRS quintile and carrier-status of rare pLOF variants in AF-associated genes. Date of inclusion was used as the index date.
Figure 2.
Figure 2.. Risk of Atrial Fibrillation (AF) over 10 Years
Absolute 10-year risk of AF by sex. The top 2 subpanels show the 10-year risk of AF for individuals with and without a predicted loss-of-function (pLOF) variant in AF-associated genes. The bottom 4 subpanels show the 10-year risk of AF in individuals according to 2 common risk factors: obesity and hypertension. The individual tiles denote absolute risk of AF within 10 years. Q indicates quintile.
Figure 3.
Figure 3.. Incident Atrial Fibrillation (AF), Cardiomyopathy, and Heart Failure According to Rare and Common Genetic Variation
Estimates from cause-specific Cox regressions according to predisposition for AF. First-incident AF, cardiomyopathy, heart failure, and all-cause mortality were considered competing events. The figure shows results from the full cohort and subgroup analyses on individuals diagnosed with AF, or cardiomyopathy or heart failure during follow-up.
See this image and copyright information in PMC

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