Jonathan D Mosley1, M Benjamin Shoemaker2, Quinn S Wells2, Dawood Darbar2, Christian M Shaffer2, Todd L Edwards2, Lisa Bastarache2, Catherine A McCarty2, Will Thompson2, Christopher G Chute2, Gail P Jarvik2, David R Crosslin2, Eric B Larson2, Iftikhar J Kullo2, Jennifer A Pacheco2, Peggy L Peissig2, Murray H Brilliant2, James G Linneman2, John S Witte2, Josh C Denny2, Dan M Roden2. 1. From the Department of Medicine (J.D.M., M.B.S., Q.S.W., C.M.S., J.C.D., D.M.R.), Vanderbilt Epidemiology Center (T.L.E.), Department of Biomedical Informatics (L.B., J.C.D., D.M.R.), Department of Pharmacology (D.M.R.), Vanderbilt University, Nashville, TN; Division of Cardiology, University of Illinois at Chicago (D.D.); Essentia Institute of Rural Health, Duluth, MN (C.A.M.); Center for Biomedical Research Informatics, NorthShore University Health System, Evanston, IL (W.T.); School of Medicine (C.G.C.), School of Public Health (C.G.C.), and School of Nursing (C.G.C.), Johns Hopkins University, Baltimore, MD; Division of Medical Genetics, Department of Medicine (G.P.J.), Department of Genome Sciences (G.P.J.), Department of Biomedical Informatics (D.R.C.), Department of Medical Education (D.R.C.), University of Washington; Group Health Research Institute, Seattle, WA (E.B.L.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.J.K.); Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (J.A.P.); Biomedical Informatics Research Center (P.L.P.), Center for Human Genetics (M.H.B., J.G.L.), Marshfield Clinic Research Foundation, WI; and Department of Epidemiology and Biostatistics, University of California, San Francisco (J.S.W.). jonathan.d.mosley@vanderbilt.edu. 2. From the Department of Medicine (J.D.M., M.B.S., Q.S.W., C.M.S., J.C.D., D.M.R.), Vanderbilt Epidemiology Center (T.L.E.), Department of Biomedical Informatics (L.B., J.C.D., D.M.R.), Department of Pharmacology (D.M.R.), Vanderbilt University, Nashville, TN; Division of Cardiology, University of Illinois at Chicago (D.D.); Essentia Institute of Rural Health, Duluth, MN (C.A.M.); Center for Biomedical Research Informatics, NorthShore University Health System, Evanston, IL (W.T.); School of Medicine (C.G.C.), School of Public Health (C.G.C.), and School of Nursing (C.G.C.), Johns Hopkins University, Baltimore, MD; Division of Medical Genetics, Department of Medicine (G.P.J.), Department of Genome Sciences (G.P.J.), Department of Biomedical Informatics (D.R.C.), Department of Medical Education (D.R.C.), University of Washington; Group Health Research Institute, Seattle, WA (E.B.L.); Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (I.J.K.); Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (J.A.P.); Biomedical Informatics Research Center (P.L.P.), Center for Human Genetics (M.H.B., J.G.L.), Marshfield Clinic Research Foundation, WI; and Department of Epidemiology and Biostatistics, University of California, San Francisco (J.S.W.).
Abstract
BACKGROUND: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. METHODS AND RESULTS: We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]). CONCLUSIONS: The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
BACKGROUND: One potential use for the PR interval is as a biomarker of disease risk. We hypothesized that quantifying the shared genetic architectures of the PR interval and a set of clinical phenotypes would identify genetic mechanisms contributing to PR variability and identify diseases associated with a genetic predictor of PR variability. METHODS AND RESULTS: We used ECG measurements from the ARIC study (Atherosclerosis Risk in Communities; n=6731 subjects) and 63 genetically modulated diseases from the eMERGE network (Electronic Medical Records and Genomics; n=12 978). We measured pairwise genetic correlations (rG) between PR phenotypes (PR interval, PR segment, P-wave duration) and each of the 63 phenotypes. The PR segment was genetically correlated with atrial fibrillation (rG=-0.88; P=0.0009). An analysis of metabolic phenotypes in ARIC also showed that the P wave was genetically correlated with waist circumference (rG=0.47; P=0.02). A genetically predicted PR interval phenotype based on 645 714 single-nucleotide polymorphisms was associated with atrial fibrillation (odds ratio=0.89 per SD change; 95% confidence interval, 0.83-0.95; P=0.0006). The differing pattern of associations among the PR phenotypes is consistent with analyses that show that the genetic correlation between the P wave and PR segment was not significantly different from 0 (rG=-0.03 [0.16]). CONCLUSIONS: The genetic architecture of the PR interval comprises modulators of atrial fibrillation risk and obesity.
Authors: Jian Yang; Beben Benyamin; Brian P McEvoy; Scott Gordon; Anjali K Henders; Dale R Nyholt; Pamela A Madden; Andrew C Heath; Nicholas G Martin; Grant W Montgomery; Michael E Goddard; Peter M Visscher Journal: Nat Genet Date: 2010-06-20 Impact factor: 38.330
Authors: Alexander Gusev; Arthur Ko; Huwenbo Shi; Gaurav Bhatia; Wonil Chung; Brenda W J H Penninx; Rick Jansen; Eco J C de Geus; Dorret I Boomsma; Fred A Wright; Patrick F Sullivan; Elina Nikkola; Marcus Alvarez; Mete Civelek; Aldons J Lusis; Terho Lehtimäki; Emma Raitoharju; Mika Kähönen; Ilkka Seppälä; Olli T Raitakari; Johanna Kuusisto; Markku Laakso; Alkes L Price; Päivi Pajukanta; Bogdan Pasaniuc Journal: Nat Genet Date: 2016-02-08 Impact factor: 38.330
Authors: Jared W Magnani; Faye L Lopez; Elsayed Z Soliman; Richard F Maclehose; Richard S Crow; Alvaro Alonso Journal: Obesity (Silver Spring) Date: 2011-04-07 Impact factor: 5.002
Authors: Catherine A McCarty; Rex L Chisholm; Christopher G Chute; Iftikhar J Kullo; Gail P Jarvik; Eric B Larson; Rongling Li; Daniel R Masys; Marylyn D Ritchie; Dan M Roden; Jeffery P Struewing; Wendy A Wolf Journal: BMC Med Genomics Date: 2011-01-26 Impact factor: 3.063
Authors: Joshua C Denny; Marylyn D Ritchie; Melissa A Basford; Jill M Pulley; Lisa Bastarache; Kristin Brown-Gentry; Deede Wang; Dan R Masys; Dan M Roden; Dana C Crawford Journal: Bioinformatics Date: 2010-03-24 Impact factor: 6.937
Authors: Alvaro Alonso; Elsayed Z Soliman; Lin Y Chen; David A Bluemke; Susan R Heckbert Journal: J Electrocardiol Date: 2013-02-26 Impact factor: 1.438
Authors: Erica Bowton; Julie R Field; Sunny Wang; Jonathan S Schildcrout; Sara L Van Driest; Jessica T Delaney; James Cowan; Peter Weeke; Jonathan D Mosley; Quinn S Wells; Jason H Karnes; Christian Shaffer; Josh F Peterson; Joshua C Denny; Dan M Roden; Jill M Pulley Journal: Sci Transl Med Date: 2014-04-30 Impact factor: 17.956
Authors: S Hong Lee; Stephan Ripke; Benjamin M Neale; Stephen V Faraone; Shaun M Purcell; Roy H Perlis; Bryan J Mowry; Anita Thapar; Michael E Goddard; John S Witte; Devin Absher; Ingrid Agartz; Huda Akil; Farooq Amin; Ole A Andreassen; Adebayo Anjorin; Richard Anney; Verneri Anttila; Dan E Arking; Philip Asherson; Maria H Azevedo; Lena Backlund; Judith A Badner; Anthony J Bailey; Tobias Banaschewski; Jack D Barchas; Michael R Barnes; Thomas B Barrett; Nicholas Bass; Agatino Battaglia; Michael Bauer; Mònica Bayés; Frank Bellivier; Sarah E Bergen; Wade Berrettini; Catalina Betancur; Thomas Bettecken; Joseph Biederman; Elisabeth B Binder; Donald W Black; Douglas H R Blackwood; Cinnamon S Bloss; Michael Boehnke; Dorret I Boomsma; Gerome Breen; René Breuer; Richard Bruggeman; Paul Cormican; Nancy G Buccola; Jan K Buitelaar; William E Bunney; Joseph D Buxbaum; William F Byerley; Enda M Byrne; Sian Caesar; Wiepke Cahn; Rita M Cantor; Miguel Casas; Aravinda Chakravarti; Kimberly Chambert; Khalid Choudhury; Sven Cichon; C Robert Cloninger; David A Collier; Edwin H Cook; Hilary Coon; Bru Cormand; Aiden Corvin; William H Coryell; David W Craig; Ian W Craig; Jennifer Crosbie; Michael L Cuccaro; David Curtis; Darina Czamara; Susmita Datta; Geraldine Dawson; Richard Day; Eco J De Geus; Franziska Degenhardt; Srdjan Djurovic; Gary J Donohoe; Alysa E Doyle; Jubao Duan; Frank Dudbridge; Eftichia Duketis; Richard P Ebstein; Howard J Edenberg; Josephine Elia; Sean Ennis; Bruno Etain; Ayman Fanous; Anne E Farmer; I Nicol Ferrier; Matthew Flickinger; Eric Fombonne; Tatiana Foroud; Josef Frank; Barbara Franke; Christine Fraser; Robert Freedman; Nelson B Freimer; Christine M Freitag; Marion Friedl; Louise Frisén; Louise Gallagher; Pablo V Gejman; Lyudmila Georgieva; Elliot S Gershon; Daniel H Geschwind; Ina Giegling; Michael Gill; Scott D Gordon; Katherine Gordon-Smith; Elaine K Green; Tiffany A Greenwood; Dorothy E Grice; Magdalena Gross; Detelina Grozeva; Weihua Guan; Hugh Gurling; Lieuwe De Haan; Jonathan L Haines; Hakon Hakonarson; Joachim Hallmayer; Steven P Hamilton; Marian L Hamshere; Thomas F Hansen; Annette M Hartmann; Martin Hautzinger; Andrew C Heath; Anjali K Henders; Stefan Herms; Ian B Hickie; Maria Hipolito; Susanne Hoefels; Peter A Holmans; Florian Holsboer; Witte J Hoogendijk; Jouke-Jan Hottenga; Christina M Hultman; Vanessa Hus; Andrés Ingason; Marcus Ising; Stéphane Jamain; Edward G Jones; Ian Jones; Lisa Jones; Jung-Ying Tzeng; Anna K Kähler; René S Kahn; Radhika Kandaswamy; Matthew C Keller; James L Kennedy; Elaine Kenny; Lindsey Kent; Yunjung Kim; George K Kirov; Sabine M Klauck; Lambertus Klei; James A Knowles; Martin A Kohli; Daniel L Koller; Bettina Konte; Ania Korszun; Lydia Krabbendam; Robert Krasucki; Jonna Kuntsi; Phoenix Kwan; Mikael Landén; Niklas Långström; Mark Lathrop; Jacob Lawrence; William B Lawson; Marion Leboyer; David H Ledbetter; Phil H Lee; Todd Lencz; Klaus-Peter Lesch; Douglas F Levinson; Cathryn M Lewis; Jun Li; Paul Lichtenstein; Jeffrey A Lieberman; Dan-Yu Lin; Don H Linszen; Chunyu Liu; Falk W Lohoff; Sandra K Loo; Catherine Lord; Jennifer K Lowe; Susanne Lucae; Donald J MacIntyre; Pamela A F Madden; Elena Maestrini; Patrik K E Magnusson; Pamela B Mahon; Wolfgang Maier; Anil K Malhotra; Shrikant M Mane; Christa L Martin; Nicholas G Martin; Manuel Mattheisen; Keith Matthews; Morten Mattingsdal; Steven A McCarroll; Kevin A McGhee; James J McGough; Patrick J McGrath; Peter McGuffin; Melvin G McInnis; Andrew McIntosh; Rebecca McKinney; Alan W McLean; Francis J McMahon; William M McMahon; Andrew McQuillin; Helena Medeiros; Sarah E Medland; Sandra Meier; Ingrid Melle; Fan Meng; Jobst Meyer; Christel M Middeldorp; Lefkos Middleton; Vihra Milanova; Ana Miranda; Anthony P Monaco; Grant W Montgomery; Jennifer L Moran; Daniel Moreno-De-Luca; Gunnar Morken; Derek W Morris; Eric M Morrow; Valentina Moskvina; Pierandrea Muglia; Thomas W Mühleisen; Walter J Muir; Bertram Müller-Myhsok; Michael Murtha; Richard M Myers; Inez Myin-Germeys; Michael C Neale; Stan F Nelson; Caroline M Nievergelt; Ivan Nikolov; Vishwajit Nimgaonkar; Willem A Nolen; Markus M Nöthen; John I Nurnberger; Evaristus A Nwulia; Dale R Nyholt; Colm O'Dushlaine; Robert D Oades; Ann Olincy; Guiomar Oliveira; Line Olsen; Roel A Ophoff; Urban Osby; Michael J Owen; Aarno Palotie; Jeremy R Parr; Andrew D Paterson; Carlos N Pato; Michele T Pato; Brenda W Penninx; Michele L Pergadia; Margaret A Pericak-Vance; Benjamin S Pickard; Jonathan Pimm; Joseph Piven; Danielle Posthuma; James B Potash; Fritz Poustka; Peter Propping; Vinay Puri; Digby J Quested; Emma M Quinn; Josep Antoni Ramos-Quiroga; Henrik B Rasmussen; Soumya Raychaudhuri; Karola Rehnström; Andreas Reif; Marta Ribasés; John P Rice; Marcella Rietschel; Kathryn Roeder; Herbert Roeyers; Lizzy Rossin; Aribert Rothenberger; Guy Rouleau; Douglas Ruderfer; Dan Rujescu; Alan R Sanders; Stephan J Sanders; Susan L Santangelo; Joseph A Sergeant; Russell Schachar; Martin Schalling; Alan F Schatzberg; William A Scheftner; Gerard D Schellenberg; Stephen W Scherer; Nicholas J Schork; Thomas G Schulze; Johannes Schumacher; Markus Schwarz; Edward Scolnick; Laura J Scott; Jianxin Shi; Paul D Shilling; Stanley I Shyn; Jeremy M Silverman; Susan L Slager; Susan L Smalley; Johannes H Smit; Erin N Smith; Edmund J S Sonuga-Barke; David St Clair; Matthew State; Michael Steffens; Hans-Christoph Steinhausen; John S Strauss; Jana Strohmaier; T Scott Stroup; James S Sutcliffe; Peter Szatmari; Szabocls Szelinger; Srinivasa Thirumalai; Robert C Thompson; Alexandre A Todorov; Federica Tozzi; Jens Treutlein; Manfred Uhr; Edwin J C G van den Oord; Gerard Van Grootheest; Jim Van Os; Astrid M Vicente; Veronica J Vieland; John B Vincent; Peter M Visscher; Christopher A Walsh; Thomas H Wassink; Stanley J Watson; Myrna M Weissman; Thomas Werge; Thomas F Wienker; Ellen M Wijsman; Gonneke Willemsen; Nigel Williams; A Jeremy Willsey; Stephanie H Witt; Wei Xu; Allan H Young; Timothy W Yu; Stanley Zammit; Peter P Zandi; Peng Zhang; Frans G Zitman; Sebastian Zöllner; Bernie Devlin; John R Kelsoe; Pamela Sklar; Mark J Daly; Michael C O'Donovan; Nicholas Craddock; Patrick F Sullivan; Jordan W Smoller; Kenneth S Kendler; Naomi R Wray Journal: Nat Genet Date: 2013-08-11 Impact factor: 38.330
Authors: Lu-Chen Weng; Amelia Weber Hall; Seung Hoan Choi; Sean J Jurgens; Jeffrey Haessler; Nathan A Bihlmeyer; Niels Grarup; Honghuang Lin; Alexander Teumer; Ruifang Li-Gao; Jie Yao; Xiuqing Guo; Jennifer A Brody; Martina Müller-Nurasyid; Katharina Schramm; Niek Verweij; Marten E van den Berg; Jessica van Setten; Aaron Isaacs; Julia Ramírez; Helen R Warren; Sandosh Padmanabhan; Jan A Kors; Rudolf A de Boer; Peter van der Meer; Moritz F Sinner; Melanie Waldenberger; Bruce M Psaty; Kent D Taylor; Uwe Völker; Jørgen K Kanters; Man Li; Alvaro Alonso; Marco V Perez; Ilonca Vaartjes; Michiel L Bots; Paul L Huang; Susan R Heckbert; Henry J Lin; Jelena Kornej; Patricia B Munroe; Cornelia M van Duijn; Folkert W Asselbergs; Bruno H Stricker; Pim van der Harst; Stefan Kääb; Annette Peters; Nona Sotoodehnia; Jerome I Rotter; Dennis O Mook-Kanamori; Marcus Dörr; Stephan B Felix; Allan Linneberg; Torben Hansen; Dan E Arking; Charles Kooperberg; Emelia J Benjamin; Kathryn L Lunetta; Patrick T Ellinor; Steven A Lubitz Journal: Circ Genom Precis Med Date: 2020-08-21
Authors: Vivian K Kawai; Mingjian Shi; Ge Liu; QiPing Feng; WeiQi Wei; Cecilia P Chung; Theresa L Walunas; Adam S Gordon; James G Linneman; Scott J Hebbring; John B Harley; Nancy J Cox; Dan M Roden; C Michael Stein; Jonathan D Mosley Journal: Lupus Date: 2021-05-12 Impact factor: 2.911