Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk
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Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk. / Vad, Oliver B; Monfort, Laia M; Paludan-Müller, Christian; Kahnert, Konstantin; Diederichsen, Søren Z; Andreasen, Laura; Lotta, Luca A; Nielsen, Jonas B; Lundby, Alicia; Svendsen, Jesper H; Olesen, Morten S; Geisinger MyCode Community Health Initiative and the Regeneron Genetics Center (RGC) Research Team.
In: JAMA Cardiology, Vol. 9, No. 8, 2024, p. 732-740.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rare and Common Genetic Variation Underlying Atrial Fibrillation Risk
AU - Vad, Oliver B
AU - Monfort, Laia M
AU - Paludan-Müller, Christian
AU - Kahnert, Konstantin
AU - Diederichsen, Søren Z
AU - Andreasen, Laura
AU - Lotta, Luca A
AU - Nielsen, Jonas B
AU - Lundby, Alicia
AU - Svendsen, Jesper H
AU - Olesen, Morten S
AU - Geisinger MyCode Community Health Initiative and the Regeneron Genetics Center (RGC) Research Team
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
U2 - 10.1001/jamacardio.2024.1528
DO - 10.1001/jamacardio.2024.1528
M3 - Journal article
C2 - 38922602
VL - 9
SP - 732
EP - 740
JO - JAMA Cardiology
JF - JAMA Cardiology
SN - 2380-6583
IS - 8
ER -
ID: 397613125