@article {8557, title = {{Genetic Risk Prediction of Atrial Fibrillation}, journal = {Circulation}, volume = {135}, year = {2017}, month = {Apr}, pages = {1311{\textendash}1320}, abstract = {Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.\ To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40\%]) and 3028 referents. Scores were based on 11 to 719 common variants ({\^a}{\textperthousand}{\textyen}5\%) associated with AF at P values ranging from <1{\~A}{\textemdash}10-3 to <1{\~A}{\textemdash}10-8 in a prior independent genetic association study.\ Incident AF occurred in 1032 individuals (5.5\%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95\% confidence interval, 1.13-1.46; P=1.5{\~A}{\textemdash}10-4) to 1.67 (25 variants; 95\% confidence interval, 1.47-1.90; P=9.3{\~A}{\textemdash}10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum {\^I}{\textquotedblright}C statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95\% confidence interval, 1.39-4.58; P=2.7{\~A}{\textemdash}10-3). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95\% confidence interval, 1.20-4.40; P=0.01).\ Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.}, author = {Lubitz, S. A. and Yin, X. and Lin, H. J. and Kolek, M. and Smith, J. G. and Trompet, S. and Rienstra, M. and Rost, N. S. and Teixeira, P. L. and Almgren, P. and Anderson, C. D. and Chen, L. Y. and Engstr?m, G. and Ford, I. and Furie, K. L. and Guo, X. and Larson, M. G. and Lunetta, K. L. and Macfarlane, P. W. and Psaty, B. M. and Soliman, E. Z. and Sotoodehnia, N. and Stott, D. J. and Taylor, K. D. and Weng, L. C. and Yao, J. and Geelhoed, B. and Verweij, N. and Siland, J. E. and Kathiresan, S. and Roselli, C. and Roden, D. M. and van der Harst, P. and Darbar, D. and Jukema, J. W. and Melander, O. and Rosand, J. and Rotter, J. I. and Heckbert, S. R. and Ellinor, P. T. and Alonso, A. and Benjamin, E. J.} } @article {8453, title = {{Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale}, journal = {Nat Genet}, volume = {52}, year = {2020}, month = {Sep}, pages = {969{\textendash}983}, abstract = {Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories and multiple complementary annotations using a dynamic weighting scheme. For the latter, we introduce {\textquoteright}annotation principal components{\textquoteright}, multidimensional summaries of in silico variant annotations. STAAR accounts for population structure and relatedness and is scalable for analyzing very large cohort and biobank whole-genome sequencing studies of continuous and dichotomous traits. We applied STAAR to identify RVs associated with four lipid traits in 12,316 discovery and 17,822 replication samples from the Trans-Omics for Precision Medicine Program. We discovered and replicated new RV associations, including disruptive missense RVs of NPC1L1 and an intergenic region near APOC1P1 associated with low-density lipoprotein cholesterol.}, author = {Li, X. and Li, Z. and Zhou, H. and Gaynor, S. M. and Liu, Y. and Chen, H. and Sun, R. and Dey, R. and Arnett, D. K. and Aslibekyan, S. and Ballantyne, C. M. and Bielak, L. F. and Blangero, J. and Boerwinkle, E. and Bowden, D. W. and Broome, J. G. and Conomos, M. P. and Correa, A. and Cupples, L. A. and Curran, J. E. and Freedman, B. I. and Guo, X. and Hindy, G. and Irvin, M. R. and Kardia, S. L. R. and Kathiresan, S. and Khan, A. T. and Kooperberg, C. L. and Laurie, C. C. and Liu, X. S. and Mahaney, M. C. and Manichaikul, A. W. and Martin, L. W. and Mathias, R. A. and McGarvey, S. T. and Mitchell, B. D. and Montasser, M. E. and Moore, J. E. and Morrison, A. C. and O{\textquoteright}Connell, J. R. and Palmer, N. D. and Pampana, A. and Peralta, J. M. and Peyser, P. A. and Psaty, B. M. and Redline, S. and Rice, K. M. and Rich, S. S. and Smith, J. A. and Tiwari, H. K. and Tsai, M. Y. and Vasan, R. S. and Wang, F. F. and Weeks, D. E. and Weng, Z. and Wilson, J. G. and Yanek, L. R. and Neale, B. M. and Sunyaev, S. R. and Abecasis, G. R. and Rotter, J. I. and Willer, C. J. and Peloso, G. M. and Natarajan, P. and Lin, X. and Abe, N. and Abecasis, G. R. and Aguet, F. and Albert, C. and Almasy, L. and Alonso, A. and Ament, S. and Anderson, P. and Anugu, P. and Applebaum-Bowden, D. and Ardlie, K. and Arking, D. and Arnett, D. K. and Ashley-Koch, A. and Aslibekyan, S. and Assimes, T. and Auer, P. and Avramopoulos, D. and Barnard, J. and Barnes, K. and Barr, R. G. and Barron-Casella, E. and Barwick, L. and Beaty, T. and Beck, G. and Becker, D. and Becker, L. and Beer, R. and Beitelshees, A. and Benjamin, E. and Benos, T. and Bezerra, M. and Bielak, L. F. and Bis, J. and Blackwell, T. and Blangero, J. and Boerwinkle, E. and Bowden, D. W. and Bowler, R. and Brody, J. and Broeckel, U. and Broome, J. G. and Bunting, K. and Burchard, E. and Bustamante, C. and Buth, E. and Cade, B. and Cardwell, J. and Carey, V. and Carty, C. and Casaburi, R. and Casella, J. and Castaldi, P. and Chaffin, M. and Chang, C. and Chang, Y. C. and Chasman, D. and Chavan, S. and Chen, B. J. and Chen, W. M. and Chen, Y. I. and Cho, M. and Choi, S. H. and Chuang, L. M. and Chung, M. and Chung, R. H. and Clish, C. and Comhair, S. and Conomos, M. P. and Cornell, E. and Correa, A. and Crandall, C. and Crapo, J. and Cupples, L. A. and Curran, J. E. and Curtis, J. and Custer, B. and Damcott, C. and Darbar, D. and Das, S. and David, S. and Davis, C. and Daya, M. and de Andrade, M. and Fuentes, L. L. and DeBaun, M. and Deka, R. and DeMeo, D. and Devine, S. and Duan, Q. and Duggirala, R. and Durda, J. P. and Dutcher, S. and Eaton, C. and Ekunwe, L. and El Boueiz, A. and Ellinor, P. and Emery, L. and Erzurum, S. and Farber, C. and Fingerlin, T. and Flickinger, M. and Fornage, M. and Franceschini, N. and Frazar, C. and Fu, M. and Fullerton, S. M. and Fulton, L. and Gabriel, S. and Gan, W. and Gao, S. and Gao, Y. and Gass, M. and Gelb, B. and Geng, X. P. and Geraci, M. and Germer, S. and Gerszten, R. and Ghosh, A. and Gibbs, R. and Gignoux, C. and Gladwin, M. and Glahn, D. and Gogarten, S. and Gong, D. W. and Goring, H. and Graw, S. and Grine, D. and Gu, C. C. and Guan, Y. and Guo, X. and Gupta, N. and Haessler, J. and Hall, M. and Harris, D. and Hawley, N. L. and He, J. and Heckbert, S. and Hernandez, R. and Herrington, D. and Hersh, C. and Hidalgo, B. and Hixson, J. and Hobbs, B. and Hokanson, J. and Hong, E. and Hoth, K. and Hsiung, C. A. and Hung, Y. J. and Huston, H. and Hwu, C. M. and Irvin, M. R. and Jackson, R. and Jain, D. and Jaquish, C. and Jhun, M. A. and Johnsen, J. and Johnson, A. and Johnson, C. and Johnston, R. and Jones, K. and Kang, H. M. and Kaplan, R. and Kardia, S. L. R. and Kathiresan, S. and Kelly, S. and Kenny, E. and Kessler, M. and Khan, A. T. and Kim, W. and Kinney, G. and Konkle, B. and Kooperberg, C. L. and Kramer, H. and Lange, C. and Lange, E. and Lange, L. and Laurie, C. C. and Laurie, C. and LeBoff, M. and Lee, J. and Lee, S. S. and Lee, W. J. and LeFaive, J. and Levine, D. and Levy, D. and Lewis, J. and Li, X. and Li, Y. and Lin, H. and Lin, H. and Lin, K. H. and Lin, X. and Liu, S. and Liu, Y. and Liu, Y. and Loos, R. J. F. and Lubitz, S. and Lunetta, K. and Luo, J. and Mahaney, M. C. and Make, B. and Manichaikul, A. W. and Manson, J. and Margolin, L. and Martin, L. W. and Mathai, S. and Mathias, R. A. and May, S. and McArdle, P. and McDonald, M. L. and McFarland, S. and McGarvey, S. T. and McGoldrick, D. and McHugh, C. and Mei, H. and Mestroni, L. and Meyers, D. A. and Mikulla, J. and Min, N. and Minear, M. and Minster, R. L. and Mitchell, B. D. and Moll, M. and Montasser, M. E. and Montgomery, C. and Moscati, A. and Musani, S. and Mwasongwe, S. and Mychaleckyj, J. C. and Nadkarni, G. and Naik, R. and Naseri, T. and Natarajan, P. and Nekhai, S. and Nelson, S. C. and Neltner, B. and Nickerson, D. and North, K. and O{\textquoteright}Connell, J. R. and O{\textquoteright}Connor, T. and Ochs-Balcom, H. and Paik, D. and Palmer, N. D. and Pankow, J. and Papanicolaou, G. and Parsa, A. and Peralta, J. M. and Perez, M. and Perry, J. and Peters, U. and Peyser, P. A. and Phillips, L. S. and Pollin, T. and Post, W. and Becker, J. P. and Boorgula, M. P. and Preuss, M. and Psaty, B. M. and Qasba, P. and Qiao, D. and Qin, Z. and Rafaels, N. and Raffield, L. and Vasan, R. S. and Rao, D. C. and Rasmussen-Torvik, L. and Ratan, A. and Redline, S. and Reed, R. and Regan, E. and Reiner, A. and Reupena, M. S. and Rice, K. M. and Rich, S. S. and Roden, D. and Roselli, C. and Rotter, J. I. and Ruczinski, I. and Russell, P. and Ruuska, S. and Ryan, K. and Sabino, E. C. and Saleheen, D. and Salimi, S. and Salzberg, S. and Sandow, K. and Sankaran, V. G. and Scheller, C. and Schmidt, E. and Schwander, K. and Schwartz, D. and Sciurba, F. and Seidman, C. and Seidman, J. and Sheehan, V. and Sherman, S. L. and Shetty, A. and Shetty, A. and Sheu, W. H. and Shoemaker, M. B. and Silver, B. and Silverman, E. and Smith, J. A. and Smith, J. and Smith, N. and Smith, T. and Smoller, S. and Snively, B. and Snyder, M. and Sofer, T. and Sotoodehnia, N. and Stilp, A. M. and Storm, G. and Streeten, E. and Su, J. L. and Sung, Y. J. and Sylvia, J. and Szpiro, A. and Sztalryd, C. and Taliun, D. and Tang, H. and Taub, M. and Taylor, K. D. and Taylor, M. and Taylor, S. and Telen, M. and Thornton, T. A. and Threlkeld, M. and Tinker, L. and Tirschwell, D. and Tishkoff, S. and Tiwari, H. K. and Tong, C. and Tracy, R. and Tsai, M. Y. and Vaidya, D. and Van Den Berg, D. and VandeHaar, P. and Vrieze, S. and Walker, T. and Wallace, R. and Walts, A. and Wang, F. F. and Wang, H. and Watson, K. and Weeks, D. E. and Weir, B. and Weiss, S. and Weng, L. C. and Wessel, J. and Willer, C. J. and Williams, K. and Williams, L. K. and Wilson, C. and Wilson, J. G. and Wong, Q. and Wu, J. and Xu, H. and Yanek, L. R. and Yang, I. and Yang, R. and Zaghloul, N. and Zekavat, M. and Zhang, Y. and Zhao, S. X. and Zhao, W. and Zhi, D. and Zhou, X. and Zhu, X. and Zody, M. and Zoellner, S. and Abdalla, M. and Abecasis, G. R. and Arnett, D. K. and Aslibekyan, S. and Assimes, T. and Atkinson, E. and Ballantyne, C. M. and Beitelshees, A. and Bielak, L. F. and Bis, J. and Bodea, C. and Boerwinkle, E. and Bowden, D. W. and Brody, J. and Cade, B. and Carlson, J. and Chang, I. S. and Chen, Y. I. and Chun, S. and Chung, R. H. and Conomos, M. P. and Correa, A. and Cupples, L. A. and Damcott, C. and de Vries, P. and Do, R. and Elliott, A. and Fu, M. and Ganna, A. and Gong, D. W. and Graham, S. and Haas, M. and Haring, B. and He, J. and Heckbert, S. and Himes, B. and Hixson, J. and Irvin, M. R. and Jain, D. and Jarvik, G. and Jhun, M. A. and Jiang, J. and Jun, G. and Kalyani, R. and Kardia, S. L. R. and Kathiresan, S. and Khera, A. and Klarin, D. and Kooperberg, C. L. and Kral, B. and Lange, L. and Laurie, C. C. and Laurie, C. and Lemaitre, R. and Li, Z. and Li, X. and Lin, X. and Mahaney, M. C. and Manichaikul, A. W. and Martin, L. W. and Mathias, R. A. and Mathur, R. and McGarvey, S. T. and McHugh, C. and McLenithan, J. and Mikulla, J. and Mitchell, B. D. and Montasser, M. E. and Moran, A. and Morrison, A. C. and Nakao, T. and Natarajan, P. and Nickerson, D. and North, K. and O{\textquoteright}Connell, J. R. and O{\textquoteright}Donnell, C. and Palmer, N. D. and Pampana, A. and Patel, A. and Peloso, G. M. and Perry, J. and Peters, U. and Peyser, P. A. and Pirruccello, J. and Pollin, T. and Preuss, M. and Psaty, B. M. and Rao, D. C. and Redline, S. and Reed, R. and Reiner, A. and Rich, S. S. and Rosenthal, S. and Rotter, J. I. and Schoenberg, J. and Selvaraj, M. S. and Sheu, W. H. and Smith, J. A. and Sofer, T. and Stilp, A. M. and Sunyaev, S. R. and Surakka, I. and Sztalryd, C. and Tang, H. and Taylor, K. D. and Tsai, M. Y. and Uddin, M. M. and Urbut, S. and Verbanck, M. and Von Holle, A. and Wang, H. and Wang, F. F. and Wiggins, K. and Willer, C. J. and Wilson, J. G. and Wolford, B. and Xu, H. and Yanek, L. R. and Zaghloul, N. and Zekavat, M. and Zhang, J.} } @article {8289, title = {{Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {01}, pages = {163}, abstract = {Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.}, author = {Shah, S. and Henry, A. and Roselli, C. and Lin, H. and Sveinbj?rnsson, G. and Fatemifar, G. and Hedman, ?. K. and Wilk, J. B. and Morley, M. P. and Chaffin, M. D. and Helgadottir, A. and Verweij, N. and Dehghan, A. and Almgren, P. and Andersson, C. and Aragam, K. G. and ?rnl?v, J. and Backman, J. D. and Biggs, M. L. and Bloom, H. L. and Brandimarto, J. and Brown, M. R. and Buckbinder, L. and Carey, D. J. and Chasman, D. I. and Chen, X. and Chen, X. and Chung, J. and Chutkow, W. and Cook, J. P. and Delgado, G. E. and Denaxas, S. and Doney, A. S. and D?rr, M. and Dudley, S. C. and Dunn, M. E. and Engstr?m, G. and Esko, T. and Felix, S. B. and Finan, C. and Ford, I. and Ghanbari, M. and Ghasemi, S. and Giedraitis, V. and Giulianini, F. and Gottdiener, J. S. and Gross, S. and Gu?bjartsson, D. F. and Gutmann, R. and Haggerty, C. M. and van der Harst, P. and Hyde, C. L. and Ingelsson, E. and Jukema, J. W. and Kavousi, M. and Khaw, K. T. and Kleber, M. E. and K?ber, L. and Koekemoer, A. and Langenberg, C. and Lind, L. and Lindgren, C. M. and London, B. and Lotta, L. A. and Lovering, R. C. and Luan, J. and Magnusson, P. and Mahajan, A. and Margulies, K. B. and M?rz, W. and Melander, O. and Mordi, I. R. and Morgan, T. and Morris, A. D. and Morris, A. P. and Morrison, A. C. and Nagle, M. W. and Nelson, C. P. and Niessner, A. and Niiranen, T. and O{\textquoteright}Donoghue, M. L. and Owens, A. T. and Palmer, C. N. A. and Parry, H. M. and Perola, M. and Portilla-Fernandez, E. and Psaty, B. M. and Rice, K. M. and Ridker, P. M. and Romaine, S. P. R. and Rotter, J. I. and Salo, P. and Salomaa, V. and van Setten, J. and Shalaby, A. A. and Smelser, D. T. and Smith, N. L. and Stender, S. and Stott, D. J. and Svensson, P. and Tammesoo, M. L. and Taylor, K. D. and Teder-Laving, M. and Teumer, A. and Thorgeirsson, G. and Thorsteinsdottir, U. and Torp-Pedersen, C. and Trompet, S. and Tyl, B. and Uitterlinden, A. G. and Veluchamy, A. and V?lker, U. and Voors, A. A. and Wang, X. and Wareham, N. J. and Waterworth, D. and Weeke, P. E. and Weiss, R. and Wiggins, K. L. and Xing, H. and Yerges-Armstrong, L. M. and Yu, B. and Zannad, F. and Zhao, J. H. and Hemingway, H. and Samani, N. J. and McMurray, J. J. V. and Yang, J. and Visscher, P. M. and Newton-Cheh, C. and Malarstig, A. and Holm, H. and Lubitz, S. A. and Sattar, N. and Holmes, M. V. and Cappola, T. P. and Asselbergs, F. W. and Hingorani, A. D. and Kuchenbaecker, K. and Ellinor, P. T. and Lang, C. C. and Stefansson, K. and Smith, J. G. and Vasan, R. S. and Swerdlow, D. I. and Lumbers, R. T. and Abecasis, G. and Backman, J. and Bai, X. and Balasubramanian, S. and Banerjee, N. and Baras, A. and Barnard, L. and Beechert, C. and Blumenfeld, A. and Cantor, M. and Chai, Y. and Chung, J. and Coppola, G. and Damask, A. and Dewey, F. and Economides, A. and Eom, G. and Forsythe, C. and Fuller, E. D. and Gu, Z. and Gurski, L. and Guzzardo, P. M. and Habegger, L. and Hahn, Y. and Hawes, A. and van Hout, C. and Jones, M. B. and Khalid, S. and Lattari, M. and Li, A. and Lin, N. and Liu, D. and Lopez, A. and Manoochehri, K. and Marchini, J. and Marcketta, A. and Maxwell, E. K. and McCarthy, S. and Mitnaul, L. J. and O{\textquoteright}Dushlaine, C. and Overton, J. D. and Padilla, M. S. and Paulding, C. and Penn, J. and Pradhan, M. and Reid, J. G. and Schleicher, T. D. and Schurmann, C. and Shuldiner, A. and Staples, J. C. and Sun, D. and Toledo, K. and Ulloa, R. H. and Widom, L. and Wolf, S. E. and Yadav, A. and Ye, B.} } @article {8925, title = {{The genomics of heart failure: design and rationale of the HERMES consortium}, journal = {ESC Heart Fail}, year = {2021}, month = {Sep}, abstract = {The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure.\ under an additive genetic model.\ HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.}, author = {Lumbers, R. T. and Shah, S. and Lin, H. and Czuba, T. and Henry, A. and Swerdlow, D. I. and Malarstig, A. and Andersson, C. and Verweij, N. and Holmes, M. V. and {\"A}rnl{\"o}v, J. and Svensson, P. and Hemingway, H. and Sallah, N. and Almgren, P. and Aragam, K. G. and Asselin, G. and Backman, J. D. and Biggs, M. L. and Bloom, H. L. and Boersma, E. and Brandimarto, J. and Brown, M. R. and Brunner-La Rocca, H. P. and Carey, D. J. and Chaffin, M. D. and Chasman, D. I. and Chazara, O. and Chen, X. and Chen, X. and Chung, J. H. and Chutkow, W. and Cleland, J. G. F. and Cook, J. P. and de Denus, S. and Dehghan, A. and Delgado, G. E. and Denaxas, S. and Doney, A. S. and D{\"o}rr, M. and Dudley, S. C. and Engstr{\"o}m, G. and Esko, T. and Fatemifar, G. and Felix, S. B. and Finan, C. and Ford, I. and Fougerousse, F. and Fouodjio, R. and Ghanbari, M. and Ghasemi, S. and Giedraitis, V. and Giulianini, F. and Gottdiener, J. S. and Gross, S. and Gu{\dh}bjartsson, D. F. and Gui, H. and Gutmann, R. and Haggerty, C. M. and van der Harst, P. and Hedman, {\r A}. K. and Helgadottir, A. and Hillege, H. and Hyde, C. L. and Jacob, J. and Jukema, J. W. and Kamanu, F. and Kardys, I. and Kavousi, M. and Khaw, K. T. and Kleber, M. E. and K{\o}ber, L. and Koekemoer, A. and Kraus, B. and Kuchenbaecker, K. and Langenberg, C. and Lind, L. and Lindgren, C. M. and London, B. and Lotta, L. A. and Lovering, R. C. and Luan, J. and Magnusson, P. and Mahajan, A. and Mann, D. and Margulies, K. B. and Marston, N. A. and M{\"a}rz, W. and McMurray, J. J. V. and Melander, O. and Melloni, G. and Mordi, I. R. and Morley, M. P. and Morris, A. D. and Morris, A. P. and Morrison, A. C. and Nagle, M. W. and Nelson, C. P. and Newton-Cheh, C. and Niessner, A. and Niiranen, T. and Nowak, C. and O{\textquoteright}Donoghue, M. L. and Owens, A. T. and Palmer, C. N. A. and Pare, G. and Perola, M. and Perreault, L. L. and Portilla-Fernandez, E. and Psaty, B. M. and Rice, K. M. and Ridker, P. M. and Romaine, S. P. R. and Roselli, C. and Rotter, J. I. and Ruff, C. T. and Sabatine, M. S. and Salo, P. and Salomaa, V. and van Setten, J. and Shalaby, A. A. and Smelser, D. T. and Smith, N. L. and Stefansson, K. and Stender, S. and Stott, D. J. and Sveinbjornsson, G. and Tammesoo, M. L. and Tardif, J. C. and Taylor, K. D. and Teder-Laving, M. and Teumer, A. and Thorgeirsson, G. and Thorsteinsdottir, U. and Torp-Pedersen, C. and Trompet, S. and Tuckwell, D. and Tyl, B. and Uitterlinden, A. G. and Vaura, F. and Veluchamy, A. and Visscher, P. M. and V{\"o}lker, U. and Voors, A. A. and Wang, X. and Wareham, N. J. and Weeke, P. E. and Weiss, R. and White, H. D. and Wiggins, K. L. and Xing, H. and Yang, J. and Yang, Y. and Yerges-Armstrong, L. M. and Yu, B. and Zannad, F. and Zhao, F. and Wilk, J. B. and Holm, H. and Sattar, N. and Lubitz, S. A. and Lanfear, D. E. and Shah, S. and Dunn, M. E. and Wells, Q. S. and Asselbergs, F. W. and Hingorani, A. D. and Dub{\'e}, M. P. and Samani, N. J. and Lang, C. C. and Cappola, T. P. and Ellinor, P. T. and Vasan, R. S. and Smith, J. G.} } @article {8829, title = {{Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {Aug}, pages = {e003300}, abstract = {Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.\ Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).\ ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70\% of carriers had normal electrocardiographic intervals.\ Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation.}, author = {Choi, S. H. and Jurgens, S. J. and Haggerty, C. M. and Hall, A. W. and Halford, J. L. and Morrill, V. N. and Weng, L. C. and Lagerman, B. and Mirshahi, T. and Pettinger, M. and Guo, X. and Lin, H. J. and Alonso, A. and Soliman, E. Z. and Kornej, J. and Lin, H. and Moscati, A. and Nadkarni, G. N. and Brody, J. A. and Wiggins, K. L. and Cade, B. E. and Lee, J. and Austin-Tse, C. and Blackwell, T. and Chaffin, M. D. and Lee, C. J. and Rehm, H. L. and Roselli, C. and Redline, S. and Mitchell, B. D. and Sotoodehnia, N. and Psaty, B. M. and Heckbert, S. R. and Loos, R. J. F. and Vasan, R. S. and Benjamin, E. J. and Correa, A. and Boerwinkle, E. and Arking, D. E. and Rotter, J. I. and Rich, S. S. and Whitsel, E. A. and Perez, M. and Kooperberg, C. and Fornwalt, B. K. and Lunetta, K. L. and Ellinor, P. T. and Lubitz, S. A.} } @article {9186, title = {{Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {09}, pages = {5144}, abstract = {250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.}, author = {Young, W. J. and Lahrouchi, N. and Isaacs, A. and Duong, T. and Foco, L. and Ahmed, F. and Brody, J. A. and Salman, R. and Noordam, R. and Benjamins, J. W. and Haessler, J. and Lyytik{\"a}inen, L. P. and Repetto, L. and Concas, M. P. and van den Berg, M. E. and Weiss, S. and Baldassari, A. R. and Bartz, T. M. and Cook, J. P. and Evans, D. S. and Freudling, R. and Hines, O. and Isaksen, J. L. and Lin, H. and Mei, H. and Moscati, A. and M{\"u}ller-Nurasyid, M. and Nursyifa, C. and Qian, Y. and Richmond, A. and Roselli, C. and Ryan, K. A. and Tarazona-Santos, E. and Th{\'e}riault, S. and van Duijvenboden, S. and Warren, H. R. and Yao, J. and Raza, D. and Aeschbacher, S. and Ahlberg, G. and Alonso, A. and Andreasen, L. and Bis, J. C. and Boerwinkle, E. and Campbell, A. and Catamo, E. and Cocca, M. and Cutler, M. J. and Darbar, D. and De Grandi, A. and De Luca, A. and Ding, J. and Ellervik, C. and Ellinor, P. T. and Felix, S. B. and Froguel, P. and Fuchsberger, C. and G{\"o}gele, M. and Graff, C. and Graff, M. and Guo, X. and Hansen, T. and Heckbert, S. R. and Huang, P. L. and Huikuri, H. V. and Hutri-K{\"a}h{\"o}nen, N. and Ikram, M. A. and Jackson, R. D. and Junttila, J. and Kavousi, M. and Kors, J. A. and Leal, T. P. and Lemaitre, R. N. and Lin, H. J. and Lind, L. and Linneberg, A. and Liu, S. and Macfarlane, P. W. and Mangino, M. and Meitinger, T. and Mezzavilla, M. and Mishra, P. P. and Mitchell, R. N. and Mononen, N. and Montasser, M. E. and Morrison, A. C. and Nauck, M. and Nauffal, V. and Navarro, P. and Nikus, K. and Pare, G. and Patton, K. K. and Pelliccione, G. and Pittman, A. and Porteous, D. J. and Pramstaller, P. P. and Preuss, M. H. and Raitakari, O. T. and Reiner, A. P. and Ribeiro, A. L. P. and Rice, K. M. and Risch, L. and Schlessinger, D. and Schotten, U. and Schurmann, C. and Shen, X. and Shoemaker, M. B. and Sinagra, G. and Sinner, M. F. and Soliman, E. Z. and Stoll, M. and Strauch, K. and Tarasov, K. and Taylor, K. D. and Tinker, A. and Trompet, S. and Uitterlinden, A. and V{\"o}lker, U. and V{\"o}lzke, H. and Waldenberger, M. and Weng, L. C. and Whitsel, E. A. and Wilson, J. G. and Avery, C. L. and Conen, D. and Correa, A. and Cucca, F. and D{\"o}rr, M. and Gharib, S. A. and Girotto, G. and Grarup, N. and Hayward, C. and Jamshidi, Y. and Jarvelin, M. R. and Jukema, J. W. and K{\"a}{\"a}b, S. and K{\"a}h{\"o}nen, M. and Kanters, J. K. and Kooperberg, C. and Lehtim{\"a}ki, T. and Lima-Costa, M. F. and Liu, Y. and Loos, R. J. F. and Lubitz, S. A. and Mook-Kanamori, D. O. and Morris, A. P. and O{\textquoteright}Connell, J. R. and Olesen, M. S. and Orini, M. and Padmanabhan, S. and Pattaro, C. and Peters, A. and Psaty, B. M. and Rotter, J. I. and Stricker, B. and van der Harst, P. and van Duijn, C. M. and Verweij, N. and Wilson, J. F. and Arking, D. E. and Ramirez, J. and Lambiase, P. D. and Sotoodehnia, N. and Mifsud, B. and Newton-Cheh, C. and Munroe, P. B.} }