@article {758, title = {Inflammation as a risk factor for atrial fibrillation.}, journal = {Circulation}, volume = {108}, year = {2003}, month = {2003 Dec 16}, pages = {3006-10}, abstract = {

BACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort.

METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5\%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4\% versus 3.7\%, adjusted OR 1.8, 95\% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16\%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95\% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95\% CI 1.11 to 1.40; P<0.001).

CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.

}, keywords = {Aged, Atrial Fibrillation, C-Reactive Protein, Cross-Sectional Studies, Female, Humans, Inflammation, Longitudinal Studies, Male, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.CIR.0000103131.70301.4F}, author = {Aviles, Ronnier J and Martin, David O and Apperson-Hansen, Carolyn and Houghtaling, Penny L and Rautaharju, Pentti and Kronmal, Richard A and Tracy, Russell P and Van Wagoner, David R and Psaty, Bruce M and Lauer, Michael S and Chung, Mina K} } @article {1170, title = {Common variants in KCNN3 are associated with lone atrial fibrillation.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Mar}, pages = {240-4}, abstract = {

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95\% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

}, keywords = {Adolescent, Adult, Aged, Atrial Fibrillation, Case-Control Studies, Cohort Studies, Female, Genome-Wide Association Study, Humans, Introns, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Small-Conductance Calcium-Activated Potassium Channels, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.537}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Glazer, Nicole L and Pfeufer, Arne and Alonso, Alvaro and Chung, Mina K and Sinner, Moritz F and de Bakker, Paul I W and Mueller, Martina and Lubitz, Steven A and Fox, Ervin and Darbar, Dawood and Smith, Nicholas L and Smith, Jonathan D and Schnabel, Renate B and Soliman, Elsayed Z and Rice, Kenneth M and Van Wagoner, David R and Beckmann, Britt-M and van Noord, Charlotte and Wang, Ke and Ehret, Georg B and Rotter, Jerome I and Hazen, Stanley L and Steinbeck, Gerhard and Smith, Albert V and Launer, Lenore J and Harris, Tamara B and Makino, Seiko and Nelis, Mari and Milan, David J and Perz, Siegfried and Esko, T{\~o}nu and K{\"o}ttgen, Anna and Moebus, Susanne and Newton-Cheh, Christopher and Li, Man and M{\"o}hlenkamp, Stefan and Wang, Thomas J and Kao, W H Linda and Vasan, Ramachandran S and N{\"o}then, Markus M and MacRae, Calum A and Stricker, Bruno H Ch and Hofman, Albert and Uitterlinden, Andr{\'e} G and Levy, Daniel and Boerwinkle, Eric and Metspalu, Andres and Topol, Eric J and Chakravarti, Aravinda and Gudnason, Vilmundur and Psaty, Bruce M and Roden, Dan M and Meitinger, Thomas and Wichmann, H-Erich and Witteman, Jacqueline C M and Barnard, John and Arking, Dan E and Benjamin, Emelia J and Heckbert, Susan R and K{\"a}{\"a}b, Stefan} } @article {1159, title = {Genome-wide association study of PR interval.}, journal = {Nat Genet}, volume = {42}, year = {2010}, month = {2010 Feb}, pages = {153-9}, abstract = {

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

}, keywords = {Aged, Atrial Fibrillation, Cohort Studies, Electrocardiography, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Conduction System, Humans, Male, Meta-Analysis as Topic}, issn = {1546-1718}, doi = {10.1038/ng.517}, author = {Pfeufer, Arne and van Noord, Charlotte and Marciante, Kristin D and Arking, Dan E and Larson, Martin G and Smith, Albert Vernon and Tarasov, Kirill V and M{\"u}ller, Martina and Sotoodehnia, Nona and Sinner, Moritz F and Verwoert, Germaine C and Li, Man and Kao, W H Linda and K{\"o}ttgen, Anna and Coresh, Josef and Bis, Joshua C and Psaty, Bruce M and Rice, Kenneth and Rotter, Jerome I and Rivadeneira, Fernando and Hofman, Albert and Kors, Jan A and Stricker, Bruno H C and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Beckmann, Britt M and Sauter, Wiebke and Gieger, Christian and Lubitz, Steven A and Newton-Cheh, Christopher and Wang, Thomas J and Magnani, Jared W and Schnabel, Renate B and Chung, Mina K and Barnard, John and Smith, Jonathan D and Van Wagoner, David R and Vasan, Ramachandran S and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Launer, Lenore J and Najjar, Samer S and Lakatta, Edward and Schlessinger, David and Uda, Manuela and Abecasis, Goncalo R and M{\"u}ller-Myhsok, Bertram and Ehret, Georg B and Boerwinkle, Eric and Chakravarti, Aravinda and Soliman, Elsayed Z and Lunetta, Kathryn L and Perz, Siegfried and Wichmann, H-Erich and Meitinger, Thomas and Levy, Daniel and Gudnason, Vilmundur and Ellinor, Patrick T and Sanna, Serena and K{\"a}{\"a}b, Stefan and Witteman, Jacqueline C M and Alonso, Alvaro and Benjamin, Emelia J and Heckbert, Susan R} } @article {1383, title = {Meta-analysis identifies six new susceptibility loci for atrial fibrillation.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Apr 29}, pages = {670-5}, abstract = {

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 {\texttimes} 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Child, Child, Preschool, European Continental Ancestry Group, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Infant, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Young Adult}, issn = {1546-1718}, doi = {10.1038/ng.2261}, author = {Ellinor, Patrick T and Lunetta, Kathryn L and Albert, Christine M and Glazer, Nicole L and Ritchie, Marylyn D and Smith, Albert V and Arking, Dan E and M{\"u}ller-Nurasyid, Martina and Krijthe, Bouwe P and Lubitz, Steven A and Bis, Joshua C and Chung, Mina K and D{\"o}rr, Marcus and Ozaki, Kouichi and Roberts, Jason D and Smith, J Gustav and Pfeufer, Arne and Sinner, Moritz F and Lohman, Kurt and Ding, Jingzhong and Smith, Nicholas L and Smith, Jonathan D and Rienstra, Michiel and Rice, Kenneth M and Van Wagoner, David R and Magnani, Jared W and Wakili, Reza and Clauss, Sebastian and Rotter, Jerome I and Steinbeck, Gerhard and Launer, Lenore J and Davies, Robert W and Borkovich, Matthew and Harris, Tamara B and Lin, Honghuang and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Milan, David J and Hofman, Albert and Boerwinkle, Eric and Chen, Lin Y and Soliman, Elsayed Z and Voight, Benjamin F and Li, Guo and Chakravarti, Aravinda and Kubo, Michiaki and Tedrow, Usha B and Rose, Lynda M and Ridker, Paul M and Conen, David and Tsunoda, Tatsuhiko and Furukawa, Tetsushi and Sotoodehnia, Nona and Xu, Siyan and Kamatani, Naoyuki and Levy, Daniel and Nakamura, Yusuke and Parvez, Babar and Mahida, Saagar and Furie, Karen L and Rosand, Jonathan and Muhammad, Raafia and Psaty, Bruce M and Meitinger, Thomas and Perz, Siegfried and Wichmann, H-Erich and Witteman, Jacqueline C M and Kao, W H Linda and Kathiresan, Sekar and Roden, Dan M and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and McKnight, Barbara and Sj{\"o}gren, Marketa and Newman, Anne B and Liu, Yongmei and Gollob, Michael H and Melander, Olle and Tanaka, Toshihiro and Stricker, Bruno H Ch and Felix, Stephan B and Alonso, Alvaro and Darbar, Dawood and Barnard, John and Chasman, Daniel I and Heckbert, Susan R and Benjamin, Emelia J and Gudnason, Vilmundur and K{\"a}{\"a}b, Stefan} } @article {6600, title = {Integrating genetic, transcriptional, and functional analyses to identify 5 novel genes for atrial fibrillation.}, journal = {Circulation}, volume = {130}, year = {2014}, month = {2014 Oct 7}, pages = {1225-35}, abstract = {

BACKGROUND: Atrial fibrillation (AF) affects >30 million individuals worldwide and is associated with an increased risk of stroke, heart failure, and death. AF is highly heritable, yet the genetic basis for the arrhythmia remains incompletely understood.

METHODS AND RESULTS: To identify new AF-related genes, we used a multifaceted approach, combining large-scale genotyping in 2 ethnically distinct populations, cis-eQTL (expression quantitative trait loci) mapping, and functional validation. Four novel loci were identified in individuals of European descent near the genes NEURL (rs12415501; relative risk [RR]=1.18; 95\% confidence interval [CI], 1.13-1.23; P=6.5{\texttimes}10(-16)), GJA1 (rs13216675; RR=1.10; 95\% CI, 1.06-1.14; P=2.2{\texttimes}10(-8)), TBX5 (rs10507248; RR=1.12; 95\% CI, 1.08-1.16; P=5.7{\texttimes}10(-11)), and CAND2 (rs4642101; RR=1.10; 95\% CI, 1.06-1.14; P=9.8{\texttimes}10(-9)). In Japanese, novel loci were identified near NEURL (rs6584555; RR=1.32; 95\% CI, 1.26-1.39; P=2.0{\texttimes}10(-25)) and CUX2 (rs6490029; RR=1.12; 95\% CI, 1.08-1.16; P=3.9{\texttimes}10(-9)). The top single-nucleotide polymorphisms or their proxies were identified as cis-eQTLs for the genes CAND2 (P=2.6{\texttimes}10(-19)), GJA1 (P=2.66{\texttimes}10(-6)), and TBX5 (P=1.36{\texttimes}10(-5)). Knockdown of the zebrafish orthologs of NEURL and CAND2 resulted in prolongation of the atrial action potential duration (17\% and 45\%, respectively).

CONCLUSIONS: We have identified 5 novel loci for AF. Our results expand the diversity of genetic pathways implicated in AF and provide novel molecular targets for future biological and pharmacological investigation.

}, keywords = {Aged, Animals, Atrial Fibrillation, Chromosome Mapping, Connexin 43, Europe, Female, Gene Knockdown Techniques, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Muscle Proteins, Nuclear Proteins, Quantitative Trait Loci, Repressor Proteins, T-Box Domain Proteins, Transcription Factors, Ubiquitin-Protein Ligases, Zebrafish, Zebrafish Proteins}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.114.009892}, author = {Sinner, Moritz F and Tucker, Nathan R and Lunetta, Kathryn L and Ozaki, Kouichi and Smith, J Gustav and Trompet, Stella and Bis, Joshua C and Lin, Honghuang and Chung, Mina K and Nielsen, Jonas B and Lubitz, Steven A and Krijthe, Bouwe P and Magnani, Jared W and Ye, Jiangchuan and Gollob, Michael H and Tsunoda, Tatsuhiko and M{\"u}ller-Nurasyid, Martina and Lichtner, Peter and Peters, Annette and Dolmatova, Elena and Kubo, Michiaki and Smith, Jonathan D and Psaty, Bruce M and Smith, Nicholas L and Jukema, J Wouter and Chasman, Daniel I and Albert, Christine M and Ebana, Yusuke and Furukawa, Tetsushi and Macfarlane, Peter W and Harris, Tamara B and Darbar, Dawood and D{\"o}rr, Marcus and Holst, Anders G and Svendsen, Jesper H and Hofman, Albert and Uitterlinden, Andr{\'e} G and Gudnason, Vilmundur and Isobe, Mitsuaki and Malik, Rainer and Dichgans, Martin and Rosand, Jonathan and Van Wagoner, David R and Benjamin, Emelia J and Milan, David J and Melander, Olle and Heckbert, Susan R and Ford, Ian and Liu, Yongmei and Barnard, John and Olesen, Morten S and Stricker, Bruno H C and Tanaka, Toshihiro and K{\"a}{\"a}b, Stefan and Ellinor, Patrick T} } @article {6820, title = {Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese.}, journal = {J Am Coll Cardiol}, volume = {63}, year = {2014}, month = {2014 Apr 1}, pages = {1200-10}, abstract = {

OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk.

BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored.

METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases).

RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements.

CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity.

}, keywords = {Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Atrial Fibrillation, Chromosome Mapping, Chromosomes, Human, Pair 4, Europe, European Continental Ancestry Group, Female, Genetic Markers, Genetic Predisposition to Disease, Homeodomain Proteins, Humans, Japan, Male, Middle Aged, Polymorphism, Single Nucleotide, Transcription Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2013.12.015}, author = {Lubitz, Steven A and Lunetta, Kathryn L and Lin, Honghuang and Arking, Dan E and Trompet, Stella and Li, Guo and Krijthe, Bouwe P and Chasman, Daniel I and Barnard, John and Kleber, Marcus E and D{\"o}rr, Marcus and Ozaki, Kouichi and Smith, Albert V and M{\"u}ller-Nurasyid, Martina and Walter, Stefan and Agarwal, Sunil K and Bis, Joshua C and Brody, Jennifer A and Chen, Lin Y and Everett, Brendan M and Ford, Ian and Franco, Oscar H and Harris, Tamara B and Hofman, Albert and K{\"a}{\"a}b, Stefan and Mahida, Saagar and Kathiresan, Sekar and Kubo, Michiaki and Launer, Lenore J and Macfarlane, Peter W and Magnani, Jared W and McKnight, Barbara and McManus, David D and Peters, Annette and Psaty, Bruce M and Rose, Lynda M and Rotter, Jerome I and Silbernagel, Guenther and Smith, Jonathan D and Sotoodehnia, Nona and Stott, David J and Taylor, Kent D and Tomaschitz, Andreas and Tsunoda, Tatsuhiko and Uitterlinden, Andr{\'e} G and Van Wagoner, David R and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Murabito, Joanne M and Sinner, Moritz F and Gudnason, Vilmundur and Felix, Stephan B and M{\"a}rz, Winfried and Chung, Mina and Albert, Christine M and Stricker, Bruno H and Tanaka, Toshihiro and Heckbert, Susan R and Jukema, J Wouter and Alonso, Alvaro and Benjamin, Emelia J and Ellinor, Patrick T} } @article {7557, title = {Fifteen Genetic Loci Associated With the Electrocardiographic P Wave.}, journal = {Circ Cardiovasc Genet}, volume = {10}, year = {2017}, month = {2017 Aug}, abstract = {

BACKGROUND: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies.

METHODS AND RESULTS: We included 44 456 individuals, of which 6778 (16\%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant (P<5{\texttimes}10-8) novel loci and replicated a prior association with SCN10A. We identified 3 loci at SCN5A, TBX5, and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction.

CONCLUSIONS: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias.

}, keywords = {Arrhythmias, Cardiac, Caveolin 1, Caveolin 2, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Genotype, Heart Atria, Humans, NAV1.5 Voltage-Gated Sodium Channel, NAV1.8 Voltage-Gated Sodium Channel, T-Box Domain Proteins}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.116.001667}, author = {Christophersen, Ingrid E and Magnani, Jared W and Yin, Xiaoyan and Barnard, John and Weng, Lu-Chen and Arking, Dan E and Niemeijer, Maartje N and Lubitz, Steven A and Avery, Christy L and Duan, Qing and Felix, Stephan B and Bis, Joshua C and Kerr, Kathleen F and Isaacs, Aaron and M{\"u}ller-Nurasyid, Martina and M{\"u}ller, Christian and North, Kari E and Reiner, Alex P and Tinker, Lesley F and Kors, Jan A and Teumer, Alexander and Petersmann, Astrid and Sinner, Moritz F and B{\r u}zkov{\'a}, Petra and Smith, Jonathan D and Van Wagoner, David R and V{\"o}lker, Uwe and Waldenberger, Melanie and Peters, Annette and Meitinger, Thomas and Limacher, Marian C and Wilhelmsen, Kirk C and Psaty, Bruce M and Hofman, Albert and Uitterlinden, Andre and Krijthe, Bouwe P and Zhang, Zhu-Ming and Schnabel, Renate B and K{\"a}{\"a}b, Stefan and van Duijn, Cornelia and Rotter, Jerome I and Sotoodehnia, Nona and D{\"o}rr, Marcus and Li, Yun and Chung, Mina K and Soliman, Elsayed Z and Alonso, Alvaro and Whitsel, Eric A and Stricker, Bruno H and Benjamin, Emelia J and Heckbert, Susan R and Ellinor, Patrick T} } @article {9907, title = {Sequencing in over 50,000 cases identifies coding and structural variation underlying atrial fibrillation risk.}, journal = {Nat Genet}, volume = {57}, year = {2025}, month = {2025 Mar}, pages = {548-562}, abstract = {

Atrial fibrillation (AF) is a prevalent and morbid abnormality of the heart rhythm with a strong genetic component. Here, we meta-analyzed genome and exome sequencing data from 36 studies that included 52,416 AF cases and 277,762 controls. In burden tests of rare coding variation, we identified novel associations between AF and the genes MYBPC3, LMNA, PKP2, FAM189A2 and KDM5B. We further identified associations between AF and rare structural variants owing to deletions in CTNNA3 and duplications of GATA4. We broadly replicated our findings in independent samples from MyCode, deCODE and UK Biobank. Finally, we found that CRISPR knockout of KDM5B in stem-cell-derived atrial cardiomyocytes led to a shortening of the action potential duration and widespread transcriptomic dysregulation of genes relevant to atrial homeostasis and conduction. Our results highlight the contribution of rare coding and structural variants to AF, including genetic links between AF and cardiomyopathies, and expand our understanding of the rare variant architecture for this common arrhythmia.

}, keywords = {Atrial Fibrillation, Case-Control Studies, Exome Sequencing, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Myocytes, Cardiac, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-025-02074-9}, author = {Choi, Seung Hoan and Jurgens, Sean J and Xiao, Ling and Hill, Matthew C and Haggerty, Christopher M and Sveinbj{\"o}rnsson, Gar{\dh}ar and Morrill, Valerie N and Marston, Nicholas A and Weng, Lu-Chen and Pirruccello, James P and Arnar, David O and Gudbjartsson, Daniel Fannar and Mantineo, Helene and von Falkenhausen, Aenne S and Natale, Andrea and Tveit, Arnljot and Geelhoed, Bastiaan and Roselli, Carolina and Van Wagoner, David R and Darbar, Dawood and Haase, Doreen and Soliman, Elsayed Z and Davogustto, Giovanni E and Jun, Goo and Calkins, Hugh and Anderson, Jeffrey L and Brody, Jennifer A and Halford, Jennifer L and Barnard, John and Hokanson, John E and Smith, Jonathan D and Bis, Joshua C and Young, Kendra and Johnson, Linda S B and Risch, Lorenz and Gula, Lorne J and Kwee, Lydia Coulter and Chaffin, Mark D and K{\"u}hne, Michael and Preuss, Michael and Gupta, Namrata and Nafissi, Navid A and Smith, Nicholas L and Nilsson, Peter M and van der Harst, Pim and Wells, Quinn S and Judy, Renae L and Schnabel, Renate B and Johnson, Renee and Smit, Roelof A J and Gabriel, Stacey and Knight, Stacey and Furukawa, Tetsushi and Blackwell, Thomas W and Nauffal, Victor and Wang, Xin and Min, Yuan-I and Yoneda, Zachary T and Laksman, Zachary W M and Bezzina, Connie R and Alonso, Alvaro and Psaty, Bruce M and Albert, Christine M and Arking, Dan E and Roden, Dan M and Chasman, Daniel I and Rader, Daniel J and Conen, David and McManus, David D and Fatkin, Diane and Benjamin, Emelia J and Boerwinkle, Eric and Marcus, Gregory M and Christophersen, Ingrid E and Smith, J Gustav and Roberts, Jason D and Raffield, Laura M and Shoemaker, M Benjamin and Cho, Michael H and Cutler, Michael J and Rienstra, Michiel and Chung, Mina K and S Olesen, Morten and Sinner, Moritz F and Sotoodehnia, Nona and Kirchhof, Paulus and Loos, Ruth J F and Nazarian, Saman and Mohanty, Sanghamitra and Damrauer, Scott M and K{\"a}{\"a}b, Stefan and Heckbert, Susan R and Redline, Susan and Shah, Svati H and Tanaka, Toshihiro and Ebana, Yusuke and Holm, Hilma and Stefansson, Kari and Ruff, Christian T and Sabatine, Marc S and Lunetta, Kathryn L and Lubitz, Steven A and Ellinor, Patrick T} }