Antoine R Baldassari1, Colleen M Sitlani2, Heather M Highland1, Dan E Arking3, Steve Buyske4, Dawood Darbar5, Rahul Gondalia1, Misa Graff1, Xiuqing Guo6,7, Susan R Heckbert8, Lucia A Hindorff9, Chani J Hodonsky1, Yii-Der Ida Chen6,7, Robert C Kaplan10, Ulrike Peters11, Wendy Post12, Alex P Reiner11, Jerome I Rotter6,7, Ralph V Shohet13, Amanda A Seyerle1, Nona Sotoodehnia8, Ran Tao14, Kent D Taylor6,7, Genevieve L Wojcik15, Jie Yao6,7, Eimear E Kenny16,17,18,19, Henry J Lin6,7, Elsayed Z Soliman20, Eric A Whitsel1, Kari E North1,21, Charles Kooperberg11, Christy L Avery1. 1. Gillings School of Global Public Health (A.R.B., H.M.H., R.G., M.G., C.J.H., A.A.S., E.A.W., K.E.N., C.L.A.), University of North Carolina at Chapel Hill. 2. Cardiovascular Health Research Unit, Department of Medicine (C.M.S.), University of Washington, Seattle.xs. 3. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (D.E.A.). 4. Department of Statistics and Biostatistics, Rutgers University, New Brunswick, NJ (S.B.). 5. Department of Medicine, University of Illinois at Chicago (D.D.). 6. Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.). 7. Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA (X.G., Y.-D.I.C., J.I.R., K.D.T., J.Y., H.J.L.). 8. Cardiovascular Health Research Unit, Division of Cardiology, Department of Medicine (S.R.H., N.S.), University of Washington, Seattle. 9. Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (L.A.H.). 10. Albert Einstein College of Medicine, Bronx, NY (R.C.K.). 11. Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA (U.P., A.P.R., C.K.). 12. Departments of Medicine and Epidemiology, Johns Hopkins University, Baltimore, MD (W.P.). 13. Center for Cardiovascular Research, John A. Burns School of Medicine, Honolulu, HI (R.V.S.). 14. Department of Biostatistics, Vanderbilt University, Nashville, TN (R.T.). 15. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (G.L.W.). 16. Center for Genomic Health (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY. 17. Charles Bronfman Institute of Personalized Medicine (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY. 18. Department of Genetics and Genomic Sciences (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY. 19. Department of Medicine (E.E.K.), Icahn School of Medicine at Mount Sinai, New York, NY. 20. Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC (E.Z.S.). 21. Carolina Center for Genome Sciences (K.E.N.), University of North Carolina at Chapel Hill.
Abstract
BACKGROUND: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. METHODS: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. RESULTS: We identified 6 novels (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (adaptive sum of powered score test P<5×10-9). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. CONCLUSIONS: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
BACKGROUND: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci. METHODS: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test. RESULTS: We identified 6 novels (CD36, PITX2, EMB, ZNF592, YPEL2, and BC043580) and 87 known loci (adaptive sum of powered score test P<5×10-9). Lead single-nucleotide polymorphism rs3211938 at CD36 was common in Blacks (minor allele frequency=10%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci. CONCLUSIONS: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.
Entities:
Keywords:
cardiovascular diseases; electrophysiology; epidemiology; genome-wide association study; population
Authors: Catherine O Johnson; Rozenn N Lemaitre; Carol E Fahrenbruch; Stephanie Hesselson; Nona Sotoodehnia; Barbara McKnight; Kenneth M Rice; Pui-Yan Kwok; David S Siscovick; Thomas D Rea Journal: Circ Cardiovasc Genet Date: 2012-06-01
Authors: Marissa LeBlanc; Verena Zuber; Bettina Kulle Andreassen; Aree Witoelar; Lingyao Zeng; Francesco Bettella; Yunpeng Wang; Linda K McEvoy; Wesley K Thompson; Andrew J Schork; Sjur Reppe; Elizabeth Barrett-Connor; Symen Ligthart; Abbas Dehghan; Kaare M Gautvik; Christopher P Nelson; Heribert Schunkert; Nilesh J Samani; Paul M Ridker; Daniel I Chasman; Pål Aukrust; Srdjan Djurovic; Arnoldo Frigessi; Rahul S Desikan; Anders M Dale; Ole A Andreassen Journal: Circ Res Date: 2015-10-20 Impact factor: 17.367
Authors: Dan E Arking; Sara L Pulit; Lia Crotti; Pim van der Harst; Patricia B Munroe; Tamara T Koopmann; Nona Sotoodehnia; Elizabeth J Rossin; Michael Morley; Xinchen Wang; Andrew D Johnson; Alicia Lundby; Daníel F Gudbjartsson; Peter A Noseworthy; Mark Eijgelsheim; Yuki Bradford; Kirill V Tarasov; Marcus Dörr; Martina Müller-Nurasyid; Annukka M Lahtinen; Ilja M Nolte; Albert Vernon Smith; Joshua C Bis; Aaron Isaacs; Stephen J Newhouse; Daniel S Evans; Wendy S Post; Daryl Waggott; Leo-Pekka Lyytikäinen; Andrew A Hicks; Lewin Eisele; David Ellinghaus; Caroline Hayward; Pau Navarro; Sheila Ulivi; Toshiko Tanaka; David J Tester; Stéphanie Chatel; Stefan Gustafsson; Meena Kumari; Richard W Morris; Åsa T Naluai; Sandosh Padmanabhan; Alexander Kluttig; Bernhard Strohmer; Andrie G Panayiotou; Maria Torres; Michael Knoflach; Jaroslav A Hubacek; Kamil Slowikowski; Soumya Raychaudhuri; Runjun D Kumar; Tamara B Harris; Lenore J Launer; Alan R Shuldiner; Alvaro Alonso; Joel S Bader; Georg Ehret; Hailiang Huang; W H Linda Kao; James B Strait; Peter W Macfarlane; Morris Brown; Mark J Caulfield; Nilesh J Samani; Florian Kronenberg; Johann Willeit; J Gustav Smith; Karin H Greiser; Henriette Meyer Zu Schwabedissen; Karl Werdan; Massimo Carella; Leopoldo Zelante; Susan R Heckbert; Bruce M Psaty; Jerome I Rotter; Ivana Kolcic; Ozren Polašek; Alan F Wright; Maura Griffin; Mark J Daly; David O Arnar; Hilma Hólm; Unnur Thorsteinsdottir; Joshua C Denny; Dan M Roden; Rebecca L Zuvich; Valur Emilsson; Andrew S Plump; Martin G Larson; Christopher J O'Donnell; Xiaoyan Yin; Marco Bobbo; Adamo P D'Adamo; Annamaria Iorio; Gianfranco Sinagra; Angel Carracedo; Steven R Cummings; Michael A Nalls; Antti Jula; Kimmo K Kontula; Annukka Marjamaa; Lasse Oikarinen; Markus Perola; Kimmo Porthan; Raimund Erbel; Per Hoffmann; Karl-Heinz Jöckel; Hagen Kälsch; Markus M Nöthen; Marcel den Hoed; Ruth J F Loos; Dag S Thelle; Christian Gieger; Thomas Meitinger; Siegfried Perz; Annette Peters; Hanna Prucha; Moritz F Sinner; Melanie Waldenberger; Rudolf A de Boer; Lude Franke; Pieter A van der Vleuten; Britt Maria Beckmann; Eimo Martens; Abdennasser Bardai; Nynke Hofman; Arthur A M Wilde; Elijah R Behr; Chrysoula Dalageorgou; John R Giudicessi; Argelia Medeiros-Domingo; Julien Barc; Florence Kyndt; Vincent Probst; Alice Ghidoni; Roberto Insolia; Robert M Hamilton; Stephen W Scherer; Jeffrey Brandimarto; Kenneth Margulies; Christine E Moravec; Fabiola del Greco M; Christian Fuchsberger; Jeffrey R O'Connell; Wai K Lee; Graham C M Watt; Harry Campbell; Sarah H Wild; Nour E El Mokhtari; Norbert Frey; Folkert W Asselbergs; Irene Mateo Leach; Gerjan Navis; Maarten P van den Berg; Dirk J van Veldhuisen; Manolis Kellis; Bouwe P Krijthe; Oscar H Franco; Albert Hofman; Jan A Kors; André G Uitterlinden; Jacqueline C M Witteman; Lyudmyla Kedenko; Claudia Lamina; Ben A Oostra; Gonçalo R Abecasis; Edward G Lakatta; Antonella Mulas; Marco Orrú; David Schlessinger; Manuela Uda; Marcello R P Markus; Uwe Völker; Harold Snieder; Timothy D Spector; Johan Ärnlöv; Lars Lind; Johan Sundström; Ann-Christine Syvänen; Mika Kivimaki; Mika Kähönen; Nina Mononen; Olli T Raitakari; Jorma S Viikari; Vera Adamkova; Stefan Kiechl; Maria Brion; Andrew N Nicolaides; Bernhard Paulweber; Johannes Haerting; Anna F Dominiczak; Fredrik Nyberg; Peter H Whincup; Aroon D Hingorani; Jean-Jacques Schott; Connie R Bezzina; Erik Ingelsson; Luigi Ferrucci; Paolo Gasparini; James F Wilson; Igor Rudan; Andre Franke; Thomas W Mühleisen; Peter P Pramstaller; Terho J Lehtimäki; Andrew D Paterson; Afshin Parsa; Yongmei Liu; Cornelia M van Duijn; David S Siscovick; Vilmundur Gudnason; Yalda Jamshidi; Veikko Salomaa; Stephan B Felix; Serena Sanna; Marylyn D Ritchie; Bruno H Stricker; Kari Stefansson; Laurie A Boyer; Thomas P Cappola; Jesper V Olsen; Kasper Lage; Peter J Schwartz; Stefan Kääb; Aravinda Chakravarti; Michael J Ackerman; Arne Pfeufer; Paul I W de Bakker; Christopher Newton-Cheh Journal: Nat Genet Date: 2014-06-22 Impact factor: 38.330
Authors: Jessica van Setten; Jennifer A Brody; Yalda Jamshidi; Brenton R Swenson; Anne M Butler; Harry Campbell; Fabiola M Del Greco; Daniel S Evans; Quince Gibson; Daniel F Gudbjartsson; Kathleen F Kerr; Bouwe P Krijthe; Leo-Pekka Lyytikäinen; Christian Müller; Martina Müller-Nurasyid; Ilja M Nolte; Sandosh Padmanabhan; Marylyn D Ritchie; Antonietta Robino; Albert V Smith; Maristella Steri; Toshiko Tanaka; Alexander Teumer; Stella Trompet; Sheila Ulivi; Niek Verweij; Xiaoyan Yin; David O Arnar; Folkert W Asselbergs; Joel S Bader; John Barnard; Josh Bis; Stefan Blankenberg; Eric Boerwinkle; Yuki Bradford; Brendan M Buckley; Mina K Chung; Dana Crawford; Marcel den Hoed; Josh C Denny; Anna F Dominiczak; Georg B Ehret; Mark Eijgelsheim; Patrick T Ellinor; Stephan B Felix; Oscar H Franco; Lude Franke; Tamara B Harris; Hilma Holm; Gandin Ilaria; Annamaria Iorio; Mika Kähönen; Ivana Kolcic; Jan A Kors; Edward G Lakatta; Lenore J Launer; Honghuang Lin; Henry J Lin; Ruth J F Loos; Steven A Lubitz; Peter W Macfarlane; Jared W Magnani; Irene Mateo Leach; Thomas Meitinger; Braxton D Mitchell; Thomas Munzel; George J Papanicolaou; Annette Peters; Arne Pfeufer; Peter P Pramstaller; Olli T Raitakari; Jerome I Rotter; Igor Rudan; Nilesh J Samani; David Schlessinger; Claudia T Silva Aldana; Moritz F Sinner; Jonathan D Smith; Harold Snieder; Elsayed Z Soliman; Timothy D Spector; David J Stott; Konstantin Strauch; Kirill V Tarasov; Unnur Thorsteinsdottir; Andre G Uitterlinden; David R Van Wagoner; Uwe Völker; Henry Völzke; Melanie Waldenberger; Harm Jan Westra; Philipp S Wild; Tanja Zeller; Alvaro Alonso; Christy L Avery; Stefania Bandinelli; Emelia J Benjamin; Francesco Cucca; Marcus Dörr; Luigi Ferrucci; Paolo Gasparini; Vilmundur Gudnason; Caroline Hayward; Susan R Heckbert; Andrew A Hicks; J Wouter Jukema; Stefan Kääb; Terho Lehtimäki; Yongmei Liu; Patricia B Munroe; Afshin Parsa; Ozren Polasek; Bruce M Psaty; Dan M Roden; Renate B Schnabel; Gianfranco Sinagra; Kari Stefansson; Bruno H Stricker; Pim van der Harst; Cornelia M van Duijn; James F Wilson; Sina A Gharib; Paul I W de Bakker; Aaron Isaacs; Dan E Arking; Nona Sotoodehnia Journal: Nat Commun Date: 2018-07-25 Impact factor: 14.919
Authors: Yun Li; Laura M Raffield; Quan Sun; Misa Graff; Bryce Rowland; Jia Wen; Le Huang; Tyne W Miller-Fleming; Jeffrey Haessler; Michael H Preuss; Jin-Fang Chai; Moa P Lee; Christy L Avery; Ching-Yu Cheng; Nora Franceschini; Xueling Sim; Nancy J Cox; Charles Kooperberg; Kari E North Journal: J Hum Genet Date: 2021-08-11 Impact factor: 3.755
Authors: Colleen M Sitlani; Antoine R Baldassari; Heather M Highland; Chani J Hodonsky; Barbara McKnight; Christy L Avery Journal: Hum Mol Genet Date: 2021-07-09 Impact factor: 6.150
Authors: Kimon Divaris; Gary D Slade; Andrea G Ferreira Zandona; John S Preisser; Jeannie Ginnis; Miguel A Simancas-Pallares; Cary S Agler; Poojan Shrestha; Deepti S Karhade; Apoena de Aguiar Ribeiro; Hunyong Cho; Yu Gu; Beau D Meyer; Ashwini R Joshi; M Andrea Azcarate-Peril; Patricia V Basta; Di Wu; Kari E North Journal: Int J Environ Res Public Health Date: 2020-11-01 Impact factor: 3.390
Authors: Usman A Tahir; Daniel H Katz; Julian Avila-Pachecho; Clary B Clish; Pradeep Natarajan; Robert E Gerszten; Alexander G Bick; Akhil Pampana; Jeremy M Robbins; Zhi Yu; Zsu-Zsu Chen; Mark D Benson; Daniel E Cruz; Debby Ngo; Shuliang Deng; Xu Shi; Shuning Zheng; Aaron S Eisman; Laurie Farrell; Michael E Hall; Adolfo Correa; Russell P Tracy; Peter Durda; Kent D Taylor; Yongmei Liu; W Craig Johnson; Xiuqing Guo; Jie Yao; Yii-Der Ida Chen; Ani W Manichaikul; Frederick L Ruberg; William S Blaner; Deepti Jain; Claude Bouchard; Mark A Sarzynski; Stephen S Rich; Jerome I Rotter; Thomas J Wang; James G Wilson Journal: Nat Commun Date: 2022-08-22 Impact factor: 17.694