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Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

ABSTRACT: Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

SUBMITTER: Christophersen IE

PROVIDER: S-EPMC5585859 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Christophersen Ingrid E IE Rienstra Michiel M Roselli Carolina C Yin Xiaoyan X Geelhoed Bastiaan B Barnard John J Lin Honghuang H Arking Dan E DE Smith Albert V AV Albert Christine M CM Chaffin Mark M Tucker Nathan R NR Li Molong M Klarin Derek D Bihlmeyer Nathan A NA Low Siew-Kee SK Weeke Peter E PE Müller-Nurasyid Martina M Smith J Gustav JG Brody Jennifer A JA Niemeijer Maartje N MN Dörr Marcus M Trompet Stella S Huffman Jennifer J Gustafsson Stefan S Schurmann Claudia C Kleber Marcus E ME Lyytikäinen Leo-Pekka LP Seppälä Ilkka I Malik Rainer R Horimoto Andrea R V R ARVR Perez Marco M Sinisalo Juha J Aeschbacher Stefanie S Thériault Sébastien S Yao Jie J Radmanesh Farid F Weiss Stefan S Teumer Alexander A Choi Seung Hoan SH Weng Lu-Chen LC Clauss Sebastian S Deo Rajat R Rader Daniel J DJ Shah Svati H SH Sun Albert A Hopewell Jemma C JC Debette Stephanie S Chauhan Ganesh G Yang Qiong Q Worrall Bradford B BB Paré Guillaume G Kamatani Yoichiro Y Hagemeijer Yanick P YP Verweij Niek N Siland Joylene E JE Kubo Michiaki M Smith Jonathan D JD Van Wagoner David R DR Bis Joshua C JC Perz Siegfried S Psaty Bruce M BM Ridker Paul M PM Magnani Jared W JW Harris Tamara B TB Launer Lenore J LJ Shoemaker M Benjamin MB Padmanabhan Sandosh S Haessler Jeffrey J Bartz Traci M TM Waldenberger Melanie M Lichtner Peter P Arendt Marina M Krieger Jose E JE Kähönen Mika M Risch Lorenz L Mansur Alfredo J AJ Peters Annette A Smith Blair H BH Lind Lars L Scott Stuart A SA Lu Yingchang Y Bottinger Erwin B EB Hernesniemi Jussi J Lindgren Cecilia M CM Wong Jorge A JA Huang Jie J Eskola Markku M Morris Andrew P AP Ford Ian I Reiner Alex P AP Delgado Graciela G Chen Lin Y LY Chen Yii-Der Ida YI Sandhu Roopinder K RK Li Man M Boerwinkle Eric E Eisele Lewin L Lannfelt Lars L Rost Natalia N Anderson Christopher D CD Taylor Kent D KD Campbell Archie A Magnusson Patrik K PK Porteous David D Hocking Lynne J LJ Vlachopoulou Efthymia E Pedersen Nancy L NL Nikus Kjell K Orho-Melander Marju M Hamsten Anders A Heeringa Jan J Denny Joshua C JC Kriebel Jennifer J Darbar Dawood D Newton-Cheh Christopher C Shaffer Christian C Macfarlane Peter W PW Heilmann-Heimbach Stefanie S Almgren Peter P Huang Paul L PL Sotoodehnia Nona N Soliman Elsayed Z EZ Uitterlinden Andre G AG Hofman Albert A Franco Oscar H OH Völker Uwe U Jöckel Karl-Heinz KH Sinner Moritz F MF Lin Henry J HJ Guo Xiuqing X Dichgans Martin M Ingelsson Erik E Kooperberg Charles C Melander Olle O Loos Ruth J F RJF Laurikka Jari J Conen David D Rosand Jonathan J van der Harst Pim P Lokki Marja-Liisa ML Kathiresan Sekar S Pereira Alexandre A Jukema J Wouter JW Hayward Caroline C Rotter Jerome I JI März Winfried W Lehtimäki Terho T Stricker Bruno H BH Chung Mina K MK Felix Stephan B SB Gudnason Vilmundur V Alonso Alvaro A Roden Dan M DM Kääb Stefan S Chasman Daniel I DI Heckbert Susan R SR Benjamin Emelia J EJ Tanaka Toshihiro T Lunetta Kathryn L KL Lubitz Steven A SA Ellinor Patrick T PT

Nature genetics 20170417 6

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115, ...[more]

PMID: 28416818

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Project description:BackgroundOptical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.MethodsParticipants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.ResultsWe recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.ConclusionsThe probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

Project description:ImportanceAtrial 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.ObjectiveTo 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 participantsThis 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.ExposuresRare pLOF variants and an AF PRS.Main outcomes and measuresRisk of AF and incident HF or CM prior to and subsequent to AF diagnosis.ResultsA 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 relevanceRare 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.

Dataset Information

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

Publications

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation.

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