Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval

Human Genetics

Volumn 134, Issue 11-12, 2015, Pages 1211-1219

  Silva, Claudia Tamar ^a,b   Kors, Jan A ^a   Amin, Najaf ^a   Dehghan, Abbas ^a   Witteman, Jacqueline C M ^a   Willemsen, Rob ^a   Oostra, Ben A ^a,c   van Duijn, Cornelia M ^a,c   Isaacs, Aaron ^a,c  

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b UNIVERSIDAD DEL ROSARIO   (Colombia)

^c Center for Medical Systems Biology   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIHYPERTENSIVE AGENT;

ADULT; ARTICLE; ASSESSMENT OF HUMANS; CLINICAL ASSESSMENT; COHORT ANALYSIS; CONTROLLED STUDY; DATA ANALYSIS SOFTWARE; ELECTROCARDIOGRAPHY; FAMILY; FAMILY STUDY; FEMALE; GENE FREQUENCY; GENE LOCUS; GENETIC ASSOCIATION; GENETIC TRAIT; GENETIC VARIABILITY; HEART ARRHYTHMIA; HEART INDEX; HEART LEFT VENTRICLE HYPERTROPHY; HERITABILITY; HUMAN; HYPERTENSION; LINKAGE ANALYSIS; MAJOR CLINICAL STUDY; MALE; MIDDLE AGED; PHENOTYPE; PR INTERVAL; PRIORITY JOURNAL; QT INTERVAL; SINGLE NUCLEOTIDE POLYMORPHISM; SOKOLOW LYON INDEX; VARIANCE; GENETIC LINKAGE; GENETIC PREDISPOSITION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; HEART; HEART RATE; PHYSIOLOGY; QUANTITATIVE TRAIT;

ADULT; COHORT STUDIES; ELECTROCARDIOGRAPHY; FEMALE; GENETIC LINKAGE; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HEART; HEART RATE; HUMANS; HYPERTROPHY, LEFT VENTRICULAR; MALE; MIDDLE AGED; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT, HERITABLE;

EID: 84946472198     PISSN: 03406717     EISSN: 14321203     Source Type: Journal    
DOI: 10.1007/s00439-015-1595-9     Document Type: Article

References (58)

1. (1999) 1999 World health organization-international society of hypertension guidelines for the management of hypertension. Guidelines subcommittee. J Hypertens 17:151–183
2. Ahnve S, Vallin H (1982) Influence of heart rate and inhibition of autonomic tone on the QT interval. Circulation 65:435–439
3. Ang D, Lang C (2008) The prognostic value of the ECG in hypertension: where are we now? J Hum Hypertens 22:460–467. doi:10.1038/jhh.2008.24
4. Arking DE, Pulit SL, Crotti L, van der Harst P, Munroe PB, Koopmann TT, Sotoodehnia N, Rossin EJ, Morley M, Wang X, Johnson AD, Lundby A, Gudbjartsson DF, Noseworthy PA, Eijgelsheim M, Bradford Y, Tarasov KV, Dorr M, Muller-Nurasyid M, Lahtinen AM, Nolte IM, Smith AV, Bis JC, Isaacs A, Newhouse SJ, Evans DS, Post WS, Waggott D, Lyytikainen LP, Hicks AA, Eisele L, Ellinghaus D, Hayward C, Navarro P, Ulivi S, Tanaka T, Tester DJ, Chatel S, Gustafsson S, Kumari M, Morris RW, Naluai AT, Padmanabhan S, Kluttig A, Strohmer B, Panayiotou AG, Torres M, Knoflach M, Hubacek JA, Slowikowski K, Raychaudhuri S, Kumar RD, Harris TB, Launer LJ, Shuldiner AR, Alonso A, Bader JS, Ehret G, Huang H, Kao WH, Strait JB, Macfarlane PW, Brown M, Caulfield MJ, Samani NJ, Kronenberg F, Willeit J, Consortium CA, Consortium C, Smith JG, Greiser KH, Meyer Zu Schwabedissen H, Werdan K, Carella M, Zelante L, Heckbert SR, Psaty BM, Rotter JI, Kolcic I, Polasek O, Wright AF, Griffin M, Daly MJ, Dcct/Edic, Arnar DO, Holm H, Thorsteinsdottir U, e MC, Denny JC, Roden DM, Zuvich RL, Emilsson V, Plump AS, Larson MG, O’Donnell CJ, Yin X, Bobbo M, D’Adamo AP, Iorio A, Sinagra G et al (2014) Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 46:826-36. doi:10.1038/ng.3014
5. Barwe SP, Jordan MC, Skay A, Inge L, Rajasekaran SA, Wolle D, Johnson CL, Neco P, Fang K, Rozengurt N, Goldhaber JI, Roos KP, Rajasekaran AK (2009) Dysfunction of ouabain-induced cardiac contractility in mice with heart-specific ablation of Na, K-ATPase beta1-subunit. J Mol Cell Cardiol 47:552–560
6. Bazett HC (1920) An analysis of the time-relations of electrocardiograms. Heart 7:353–370
7. Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Miller DH, Chaudhary BS, Phillips MC (1985) Electrocardiographic detection of left ventricular hypertrophy: development and prospective validation of improved criteria. J Am Coll Cardiol 6:572–580
8. Cerra MC, Imbrogno S (2012) Phospholamban and cardiac function: a comparative perspective in vertebrates. Acta Physiol (Oxf). doi:10.1111/j.1748-1716.2012.02389.x
9. Chopra SS, Stroud DM, Watanabe H, Bennett JS, Burns CG, Wells KS, Yang T, Zhong TP, Roden DM (2010) Voltage-gated sodium channels are required for heart development in zebrafish. Circ Res 106:1342–1350
10. Dalageorgou C, Ge D, Jamshidi Y, Nolte IM, Riese H, Savelieva I, Carter ND, Spector TD, Snieder H (2008) Heritability of QT interval: how much is explained by genes for resting heart rate? J Cardiovasc Electrophysiol 19:386–391
11. de Bruyne MC, Kors JA, Hoes AW, Kruijssen DA, Deckers JW, Grosfeld M, van Herpen G, Grobbee DE, van Bemmel JH (1997) Diagnostic interpretation of electrocardiograms in population-based research: computer program research physicians, or cardiologists? J Clin Epidemiol 50:947–952
12. DeFilippis AP, Larned JM, Cole JH, Nell-Dybdahl C, Miller JI 3rd, Sperling LS (2007) Clues to cardiovascular risk: an office-based approach. Prev Cardiol 10:36–41
13. Dekker JM, Crow RS, Hannan PJ, Schouten EG, Folsom AR, Study A (2004) Heart rate-corrected QT interval prolongation predicts risk of coronary heart disease in black and white middle-aged men and women: the ARIC study. J Am Coll Cardiol 43:565–571. doi:10.1016/j.jacc.2003.09.040
14. Eijgelsheim M, Aarnoudse AL, Rivadeneira F, Kors JA, Witteman JC, Hofman A, van Duijn CM, Uitterlinden AG, Stricker BH (2009) Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration. Hum Mol Genet 18:347–357. doi:10.1093/hmg/ddn341
15. Gussak I, Brugada P, Brugada J, Wright RS, Kopecky SL, Chaitman BR, Bjerregaard P (2000) Idiopathic short QT interval: a new clinical syndrome? Cardiology 94:99–102
16. Haarmark C, Kyvik KO, Vedel-Larsen E, Budtz-Jorgensen E, Kanters JK (2011) Heritability of Tpeak-Tend interval and T-wave amplitude: a twin study. Circ Cardiovasc Genet 4:516–522. doi:10.1161/CIRCGENETICS.111.959551
17. Havlik RJ, Garrison RJ, Fabsitz R, Feinleib M (1980) Variability of heart rate, P-R, QRS and Q-T durations in twins. J Electrocardiol 13:45–48
18. Holm H, Gudbjartsson DF, Arnar DO, Thorleifsson G, Thorgeirsson G, Stefansdottir H, Gudjonsson SA, Jonasdottir A, Mathiesen EB, Njolstad I, Nyrnes A, Wilsgaard T, Hald EM, Hveem K, Stoltenberg C, Lochen ML, Kong A, Thorsteinsdottir U, Stefansson K (2010) Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet 42:117–122. doi:10.1038/ng.511
19. Im SW, Lee MK, Lee HJ, Oh SI, Kim HL, Sung J, Cho SI, Seo JS, Kim JI (2009) Analysis of genetic and non-genetic factors that affect the QTc interval in a Mongolian population: the GENDISCAN study. Exp Mol Med 41:841–848
20. Isaacs A, Sayed-Tabatabaei FA, Aulchenko YS, Zillikens MC, Sijbrands EJ, Schut AF, Rutten WP, Pols HA, Witteman JC, Oostra BA, van Duijn CM (2007) Heritabilities, apolipoprotein E, and effects of inbreeding on plasma lipids in a genetically isolated population: the Erasmus Rucphen Family study. Eur J Epidemiol 22:99–105
21. Kolder IC, Tanck MW, Bezzina CR (2012) Common genetic variation modulating cardiac ECG parameters and susceptibility to sudden cardiac death. J Mol Cell Cardiol 52:620–629. doi:10.1016/j.yjmcc.2011.12.014
22. Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR (2010) MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34:816–834
23. Malik M (2004) Errors and misconceptions in ECG measurement used for the detection of drug induced QT interval prolongation. J Electrocardiol 37(Suppl):25–33
24. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM (2009) Finding the missing heritability of complex diseases. Nature 461:747–753
25. Marian AJ (2012) Elements of ‘missing heritability. Curr Opin Cardiol 27:197–201
26. Marroni F, Pfeufer A, Aulchenko YS, Franklin CS, Isaacs A, Pichler I, Wild SH, Oostra BA, Wright AF, Campbell H, Witteman JC, Kaab S, Hicks AA, Gyllensten U, Rudan I, Meitinger T, Pattaro C, van Duijn CM, Wilson JF, Pramstaller PP, Consortium E (2009) A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations: the EUROSPAN project. Circ Cardiovasc Genet 2:322–328. doi:10.1161/CIRCGENETICS.108.833806
27. Mayosi BM, Keavney B, Kardos A, Davies CH, Ratcliffe PJ, Farrall M, Watkins H (2002) Electrocardiographic measures of left ventricular hypertrophy show greater heritability than echocardiographic left ventricular mass. Eur Heart J 23:1963–1971
28. Medeiros A, Biagi DG, Sobreira TJ, de Oliveira PS, Negrao CE, Mansur AJ, Krieger JE, Brum PC, Pereira AC (2011) Mutations in the human phospholamban gene in patients with heart failure. Am Heart J 162(1088–95):e1
29. Milan DJ, Lubitz SA, Kaab S, Ellinor PT (2010) Genome-wide association studies in cardiac electrophysiology: recent discoveries and implications for clinical practice. Heart Rhythm 7:1141–1148
30. Molloy TJ, Okin PM, Devereux RB, Kligfield P (1992) Electrocardiographic detection of left ventricular hypertrophy by the simple QRS voltage-duration product. J Am Coll Cardiol 20:1180–1186
31. Mourad JJ (2008) The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target. Vasc Health Risk Manag 4:1315–1325
32. Mutikainen S, Ortega-Alonso A, Alen M, Kaprio J, Karjalainen J, Rantanen T, Kujala UM (2009a) Electrocardiographic indices of left ventricular hypertrophy and repolarization phase share the same genetic influences: a twin study. Ann Noninvasive Electrocardiol 14:346–354
33. Mutikainen S, Ortega-Alonso A, Alen M, Kaprio J, Karjalainen J, Rantanen T, Kujala UM (2009b) Genetic influences on resting electrocardiographic variables in older women: a twin study. Ann Noninvasive Electrocardiol 14:57–64
34. Newton-Cheh C, Larson MG, Corey DC, Benjamin EJ, Herbert AG, Levy D, D’Agostino RB, O’Donnell CJ (2005) QT interval is a heritable quantitative trait with evidence of linkage to chromosome 3 in a genome-wide linkage analysis: the Framingham Heart Study. Heart Rhythm 2:277–284
35. Newton-Cheh C, Guo CY, Wang TJ, O’Donnell CJ, Levy D, Larson MG (2007) Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study. BMC Med Genet 8(Suppl 1):S7. doi:10.1186/1471-2350-8-S1-S7
36. Newton-Cheh C, Eijgelsheim M, Rice KM, de Bakker PI, Yin X, Estrada K, Bis JC, Marciante K, Rivadeneira F, Noseworthy PA, Sotoodehnia N, Smith NL, Rotter JI, Kors JA, Witteman JC, Hofman A, Heckbert SR, O’Donnell CJ, Uitterlinden AG, Psaty BM, Lumley T, Larson MG, Stricker BH (2009) Common variants at ten loci influence QT interval duration in the QTGEN study. Nat Genet 41:399–406. doi:10.1038/ng.364
37. Nolte IM, Wallace C, Newhouse SJ, Waggott D, Fu J, Soranzo N, Gwilliam R, Deloukas P, Savelieva I, Zheng D, Dalageorgou C, Farrall M, Samani NJ, Connell J, Brown M, Dominiczak A, Lathrop M, Zeggini E, Wain LV, Wellcome Trust Case Control C, Group DER, Newton-Cheh C, Eijgelsheim M, Rice K, de Bakker PI, consortium Q, Pfeufer A, Sanna S, Arking DE, consortium Q, Asselbergs FW, Spector TD, Carter ND, Jeffery S, Tobin M, Caulfield M, Snieder H, Paterson AD, Munroe PB, Jamshidi Y (2009) Common genetic variation near the phospholamban gene is associated with cardiac repolarisation: meta-analysis of three genome-wide association studies. PLoS One 4:e6138
38. Pardo LM, MacKay I, Oostra B, van Duijn CM, Aulchenko YS (2005) The effect of genetic drift in a young genetically isolated population. Ann Hum Genet 69:288–295
39. Pfeufer A, Sanna S, Arking DE, Muller M, Gateva V, Fuchsberger C, Ehret GB, Orru M, Pattaro C, Kottgen A, Perz S, Usala G, Barbalic M, Li M, Putz B, Scuteri A, Prineas RJ, Sinner MF, Gieger C, Najjar SS, Kao WH, Muhleisen TW, Dei M, Happle C, Mohlenkamp S, Crisponi L, Erbel R, Jockel KH, Naitza S, Steinbeck G, Marroni F, Hicks AA, Lakatta E, Muller-Myhsok B, Pramstaller PP, Wichmann HE, Schlessinger D, Boerwinkle E, Meitinger T, Uda M, Coresh J, Kaab S, Abecasis GR, Chakravarti A (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD study. Nat Genet 41:407–414. doi:10.1038/ng.362
40. Pfeufer A, van Noord C, Marciante KD, Arking DE, Larson MG, Smith AV, Tarasov KV, Muller M, Sotoodehnia N, Sinner MF, Verwoert GC, Li M, Kao WH, Kottgen A, Coresh J, Bis JC, Psaty BM, Rice K, Rotter JI, Rivadeneira F, Hofman A, Kors JA, Stricker BH, Uitterlinden AG, van Duijn CM, Beckmann BM, Sauter W, Gieger C, Lubitz SA, Newton-Cheh C, Wang TJ, Magnani JW, Schnabel RB, Chung MK, Barnard J, Smith JD, Van Wagoner DR, Vasan RS, Aspelund T, Eiriksdottir G, Harris TB, Launer LJ, Najjar SS, Lakatta E, Schlessinger D, Uda M, Abecasis GR, Muller-Myhsok B, Ehret GB, Boerwinkle E, Chakravarti A, Soliman EZ, Lunetta KL, Perz S, Wichmann HE, Meitinger T, Levy D, Gudnason V, Ellinor PT, Sanna S, Kaab S, Witteman JC, Alonso A, Benjamin EJ, Heckbert SR (2010) Genome-wide association study of PR interval. Nat Genet 42:153–159. doi:10.1038/ng.517
41. Qu X, Jia H, Garrity DM, Tompkins K, Batts L, Appel B, Zhong TP, Baldwin HS (2008) Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev Biol 317:486–496
42. Roguin A (2011) Henry Cuthbert Bazett (1885–1950)—the man behind the QT interval correction formula. Pacing Clin Electrophysiol 34:384–388. doi:10.1111/j.1540-8159.2010.02973.x
43. Russell MW, Law I, Sholinsky P, Fabsitz RR (1998) Heritability of ECG measurements in adult male twins. J Electrocardiol 30(Suppl):64–68
44. Sayed-Tabatabaei FA, van Rijn MJ, Schut AF, Aulchenko YS, Croes EA, Zillikens MC, Pols HA, Witteman JC, Oostra BA, van Duijn CM (2005) Heritability of the function and structure of the arterial wall: findings of the Erasmus Rucphen Family (ERF) study. Stroke 36:2351–2356. doi:10.1161/01.STR.0000185719.66735.dd
45. Schwartz PJ, Wolf S (1978) QT interval prolongation as predictor of sudden death in patients with myocardial infarction. Circulation 57:1074–1077
46. Shah S, Nelson CP, Gaunt TR, van der Harst P, Barnes T, Braund PS, Lawlor DA, Casas JP, Padmanabhan S, Drenos F, Kivimaki M, Talmud PJ, Humphries SE, Whittaker J, Morris RW, Whincup PH, Dominiczak A, Munroe PB, Johnson T, Goodall AH, Cambien F, Diemert P, Hengstenberg C, Ouwehand WH, Felix JF, Glazer NL, Tomaszewski M, Burton PR, Tobin MD, van Veldhuisen DJ, de Boer RA, Navis G, van Gilst WH, Mayosi BM, Thompson JR, Kumari M, MacFarlane PW, Day IN, Hingorani AD, Samani NJ (2011) Four genetic loci influencing electrocardiographic indices of left ventricular hypertrophy. Circ Cardiovasc Genet 4:626–635. doi:10.1161/CIRCGENETICS.111.960203
47. Siegel RJ, Roberts WC (1982) Electrocardiographic observations in severe aortic valve stenosis: correlative necropsy study to clinical, hemodynamic, and ECG variables demonstrating relation of 12-lead QRS amplitude to peak systolic transaortic pressure gradient. Am Heart J 103:210–221
48. Sleegers K, de Koning I, Aulchenko YS, van Rijn MJ, Houben MP, Croes EA, van Swieten JC, Oostra BA, van Duijn CM (2007) Cerebrovascular risk factors do not contribute to genetic variance of cognitive function: the ERF study. Neurobiol Aging 28:735–741
49. Smith JG, Lowe JK, Kovvali S, Maller JB, Salit J, Daly MJ, Stoffel M, Altshuler DM, Friedman JM, Breslow JL, Newton-Cheh C (2009) Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae. Heart Rhythm 6:634–641
50. Sokolow M, Lyon TP (1949) The ventricular complex in right ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 38:273–294
51. Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW (2013) Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet 14:483–495. doi:10.1038/nrg3461
52. Sotoodehnia N, Isaacs A, de Bakker PI, Dorr M, Newton-Cheh C, Nolte IM, van der Harst P, Muller M, Eijgelsheim M, Alonso A, Hicks AA, Padmanabhan S, Hayward C, Smith AV, Polasek O, Giovannone S, Fu J, Magnani JW, Marciante KD, Pfeufer A, Gharib SA, Teumer A, Li M, Bis JC, Rivadeneira F, Aspelund T, Kottgen A, Johnson T, Rice K, Sie MP, Wang YA, Klopp N, Fuchsberger C, Wild SH, Mateo Leach I, Estrada K, Volker U, Wright AF, Asselbergs FW, Qu J, Chakravarti A, Sinner MF, Kors JA, Petersmann A, Harris TB, Soliman EZ, Munroe PB, Psaty BM, Oostra BA, Cupples LA, Perz S, de Boer RA, Uitterlinden AG, Volzke H, Spector TD, Liu FY, Boerwinkle E, Dominiczak AF, Rotter JI, van Herpen G, Levy D, Wichmann HE, van Gilst WH, Witteman JC, Kroemer HK, Kao WH, Heckbert SR, Meitinger T, Hofman A, Campbell H, Folsom AR, van Veldhuisen DJ, Schwienbacher C, O’Donnell CJ, Volpato CB, Caulfield MJ, Connell JM, Launer L, Lu X, Franke L, Fehrmann RS, te Meerman G, Groen HJ, Weersma RK, van den Berg LH, Wijmenga C, Ophoff RA, Navis G, Rudan I, Snieder H, Wilson JF, Pramstaller PP, Siscovick DS, Wang TJ, Gudnason V, van Duijn CM, Felix SB, Fishman GI, Jamshidi Y, Stricker BH et al (2010) Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet 42:1068–1076
53. Straus SM, Kors JA, De Bruin ML, van der Hooft CS, Hofman A, Heeringa J, Deckers JW, Kingma JH, Sturkenboom MC, Stricker BH, Witteman JC (2006) Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 47:362–367. doi:10.1016/j.jacc.2005.08.067
54. Teodorescu C, Reinier K, Uy-Evanado A, Navarro J, Mariani R, Gunson K, Jui J, Chugh SS (2011) Prolonged QRS duration on the resting ECG is associated with sudden death risk in coronary disease, independent of prolonged ventricular repolarization. Heart Rhythm 8:1562–1567. doi:10.1016/j.hrthm.2011.06.011
55. Tin LL, Beevers DG, Lip GY (2002) Systolic vs diastolic blood pressure and the burden of hypertension. J Hum Hypertens 16:147–150. doi:10.1038/sj.jhh.1001373
56. van Bemmel JH, Kors JA, van Herpen G (1990) Methodology of the modular ECG analysis system MEANS. Methods Inf Med 29:346–353
57. Willems JL, Arnaud P, van Bemmel JH, Bourdillon PJ, Degani R, Denis B, Graham I, Harms FM, Macfarlane PW, Mazzocca G et al (1987) A reference data base for multilead electrocardiographic computer measurement programs. J Am Coll Cardiol 10:1313–1321
58. Willems JL, Abreu-Lima C, Arnaud P, van Bemmel JH, Brohet C, Degani R, Denis B, Gehring J, Graham I, van Herpen G et al (1991) The diagnostic performance of computer programs for the interpretation of electrocardiograms. N Engl J Med 325:1767–1773. doi:10.1056/NEJM199112193252503