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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2007

Open Access 01-09-2007 | Research

Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

Authors: Christopher Newton-Cheh, Chao-Yu Guo, Thomas J Wang, Christopher J O'Donnell, Daniel Levy, Martin G Larson

Published in: BMC Medical Genetics | Special Issue 1/2007

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Abstract

Background

Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.

Methods

Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).

Results

Associations at p < 10-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10-3; lowest p-value, rs6683968, p = 1 × 10-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://​www.​ncbi.​nlm.​nih.​gov/​projects/​gap/​cgi-bin/​study.​cgi?​id=​phs000007.

Conclusion

In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.
Literature
1.
Kannel WB, McGee DL, Schatzkin A: An epidemiological perspective of sudden death. 26-year follow-up in the Framingham Study. Drugs. 1984, 28 (Suppl 1): 1-16.CrossRefPubMed
2.
Algra A, Tijssen JG, Roelandt JR, Pool J, Lubsen J: QTc prolongation measured by standard 12-lead electrocardiography is an independent risk factor for sudden death due to cardiac arrest. Circulation. 1991, 83: 1888-1894.CrossRefPubMed
3.
Schouten EG, Dekker JM, Meppelink P, Kok FJ, Vandenbroucke JP, Pool J: QT interval prolongation predicts cardiovascular mortality in an apparently healthy population. Circulation. 1991, 84: 1516-1523.CrossRefPubMed
4.
Gillman MW, Kannel WB, Belanger A, D'Agostino RB: Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J. 1993, 125: 1148-1154. 10.1016/0002-8703(93)90128-V.CrossRefPubMed
5.
Jouven X, Zureik M, Desnos M, Guerot C, Ducimetiere P: Resting heart rate as a predictive risk factor for sudden death in middle-aged men. Cardiovasc Res. 2001, 50: 373-378. 10.1016/S0008-6363(01)00230-9.CrossRefPubMed
6.
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: Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006, 47: 362-367. 10.1016/j.jacc.2005.08.067.CrossRefPubMed
7.
Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D: Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994, 90: 878-883.CrossRefPubMed
8.
Busjahn A, Knoblauch H, Faulhaber HD, Boeckel T, Rosenthal M, Uhlmann R, Hoehe M, Schuster H, Luft FC: QT interval is linked to 2 long-QT syndrome loci in normal subjects. Circulation. 1999, 99: 3161-3164.CrossRefPubMed
9.
Newton-Cheh C, Larson MG, Corey DC, Benjamin EJ, Herbert AG, Levy D, D'Agostino RB, O'Donnell CJ: 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. 2005, 2: 277-284. 10.1016/j.hrthm.2004.11.009.CrossRefPubMed
10.
Wise NB, Comequi WJ, White PD: An electrocardiographic study of twins. American Heart Journal. 1939, 17: 701-710. 10.1016/S0002-8703(39)90436-9.CrossRef
11.
Hanson B, Tuna N, Bouchard T, Heston L, Eckert E, Lykken D, Segal N, Rich S: Genetic factors in the electrocardiogram and heart rate of twins reared apart and together. Am J Cardiol. 1989, 63: 606-609. 10.1016/0002-9149(89)90907-7.CrossRefPubMed
12.
An P, Rice T, Gagnon J, Borecki IB, Perusse L, Leon AS, Skinner JS, Wilmore JH, Bouchard C, Rao DC: Familial aggregation of resting blood pressure and heart rate in a sedentary population: the HERITAGE Family Study. Health, Risk Factors, Exercise Training, and Genetics. Am J Hypertens. 1999, 12: 264-270. 10.1016/S0895-7061(98)00261-1.CrossRefPubMed
13.
Ranade K, Jorgenson E, Sheu WH, Pei D, Hsiung CA, Chiang FT, Chen YD, Pratt R, Olshen RA, Curb D, Cox DR, Botstein D, Risch N: A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate. Am J Hum Genet. 2002, 70: 935-942. 10.1086/339621.PubMedCentralCrossRefPubMed
14.
Russell MW, Law I, Sholinsky P, Fabsitz RR: Heritability of ECG measurements in adult male twins. J Electrocardiol. 1998, 30 (Suppl): 64-68. 10.1016/S0022-0736(98)80034-4.CrossRefPubMed
15.
Havlik RJ, Garrison RJ, Fabsitz R, Feinleib M: Variability of heart rate, P-R, QRS and Q-T durations in twins. J Electrocardiol. 1980, 13: 45-48. 10.1016/S0022-0736(80)80008-2.CrossRefPubMed
16.
Singh JP, Larson MG, O'Donnell CJ, Tsuji H, Evans JC, Levy D: Heritability of heart rate variability: the Framingham Heart Study. Circulation. 1999, 99: 2251-2254.CrossRefPubMed
17.
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J: Complement factor H polymorphism in age-related macular degeneration. Science. 2005, 308: 385-389. 10.1126/science.1109557.PubMedCentralCrossRefPubMed
18.
Herbert AG, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, Wichmann HE, Meitinger T, Hunter D, Hu FB, Colditz G, Hinney A, Hebebrand J, Koberwitz K, Zhu X, Cooper R, Ardlie K, Lyon HN, Hirschhorn JN, Laird NM, Lenburg ME, Lange C, Christman MF: A Common Genetic Variant is Associated With Adult and Childhood Obesity. Science. 2006, 312: 279-283. 10.1126/science.1124779.CrossRefPubMed
19.
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH: A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006, 314: 1461-1463. 10.1126/science.1135245.PubMedCentralCrossRefPubMed
20.
Arking DE, Pfeufer A, Post W, Kao WH, Newton-Cheh C, Ikeda M, West K, Kashuk C, Akyol M, Perz S, Jalilzadeh S, Illig T, Gieger C, Guo CY, Larson MG, Wichmann HE, Marban E, O'Donnell CJ, Hirschhorn JN, Kaab S, Spooner PM, Meitinger T, Chakravarti A: A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006, 38: 644-651. 10.1038/ng1790.CrossRefPubMed
21.
Pe'er I, de Bakker PI, Maller J, Yelensky R, Altshuler D, Daly MJ: Evaluating and improving power in whole-genome association studies using fixed marker sets. Nat Genet. 2006, 38: 663-667. 10.1038/ng1816.CrossRefPubMed
22.
Cupples LA, Arruda H, Benjamin EJ, D'Agostino RB, Demissie S, DeStefano AL, Dupuis J, Falls K, Fox CS, Gottlieb DJ, Govindaraju DR, Guo CY, Heard-Costa N, Hwang SJ, Kathiresan S, Kiel DP, Laramie JM, Larson MG, Levy D, Liu CY, Lunetta KL, Mailman MD, Manning AK, Meigs JB, Murabito JM, Newton-Cheh C, O'Connor GT, O'Donnell CJ, Pandey MA, Seshadri S, Vasan RS, Wang ZY, Wilk JB, Wolf PA, Yang Q, Atwood LD: The Framingham Heart Study 100K SNP genome-wide association study resource: Overview of 17 phenotype working group reports. BMC Med Genet. 2007, 8 (Suppl 1): S1-PubMedCentralCrossRefPubMed
23.
Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D: Determinants of heart rate variability. J Am Coll Cardiol. 1996, 28: 1539-1546. 10.1016/S0735-1097(96)00342-7.CrossRefPubMed
24.
Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D: The human genome browser at UCSC. Genome Res. 2002, 12: 996-1006. 10.1101/gr.229102. Article published online before print in May 2002.PubMedCentralCrossRefPubMed
25.
Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ, Weber RJ, Haussler D, Kent WJ: The UCSC Genome Browser Database. Nucleic Acids Res. 2003, 31: 51-54. 10.1093/nar/gkg129.PubMedCentralCrossRefPubMed
26.
27.
Horvath S, Xu X, Laird NM: The family based association test method: strategies for studying general genotype – phenotype associations. Eur J Hum Genet. 2001, 9: 301-306. 10.1038/sj.ejhg.5200625.CrossRefPubMed
28.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR: Merlin – rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet. 2002, 30: 97-101. 10.1038/ng786.CrossRefPubMed
29.
Skol AD, Scott LJ, Abecasis GR, Boehnke M: Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006, 38: 209-213. 10.1038/ng1706.CrossRefPubMed
30.
Hirschhorn JN, Daly MJ: Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005, 6: 95-108. 10.1038/nrg1521.CrossRefPubMed
Metadata
Title
Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study
Authors
Christopher Newton-Cheh
Chao-Yu Guo
Thomas J Wang
Christopher J O'Donnell
Daniel Levy
Martin G Larson
Publication date
01-09-2007
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue Special Issue 1/2007
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-8-S1-S7

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