Genome-Wide Association Studies of the PR Interval in African Americans

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The PR interval on the electrocardiogram reflects atrial and atrioventricular nodal conduction time. The PR interval is heritable, provides important information about arrhythmia risk, and has been suggested to differ among human races. Genome-wide association (GWA) studies have identified common genetic determinants of the PR interval in individuals of European and Asian ancestry, but there is a general paucity of GWA studies in individuals of African ancestry. We performed GWA studies in African American individuals from four cohorts (n = 6,247) to identify genetic variants associated with PR interval duration. Genotyping was performed using the Affymetrix 6.0 microarray. Imputation was performed for 2.8 million single nucleotide polymorphisms (SNPs) using combined YRI and CEU HapMap phase II panels. We observed a strong signal (rs3922844) within the gene encoding the cardiac sodium channel (SCN5A) with genome-wide significant association (p<2.5×10⁻⁸) in two of the four cohorts and in the meta-analysis. The signal explained 2% of PR interval variability in African Americans (beta = 5.1 msec per minor allele, 95% CI = 4.1–6.1, p = 3×10⁻²³). This SNP was also associated with PR interval (beta = 2.4 msec per minor allele, 95% CI = 1.8–3.0, p = 3×10⁻¹⁶) in individuals of European ancestry (n = 14,042), but with a smaller effect size (p for heterogeneity <0.001) and variability explained (0.5%). Further meta-analysis of the four cohorts identified genome-wide significant associations with SNPs in SCN10A (rs6798015), MEIS1 (rs10865355), and TBX5 (rs7312625) that were highly correlated with SNPs identified in European and Asian GWA studies. African ancestry was associated with increased PR duration (13.3 msec, p = 0.009) in one but not the other three cohorts. Our findings demonstrate the relevance of common variants to African Americans at four loci previously associated with PR interval in European and Asian samples and identify an association signal at one of these loci that is more strongly associated with PR interval in African Americans than in Europeans.

Vyšlo v časopise: Genome-Wide Association Studies of the PR Interval in African Americans. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001304
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001304

Souhrn

Zdroje

1. ChengS

KeyesMJ

LarsonMG

McCabeEL

Newton-ChehC

2009 Long-term outcomes in individuals with prolonged PR interval or first-degree atrioventricular block. JAMA 301 2571 2577

2. HavlikRJ

GarrisonRJ

FabsitzR

FeinleibM

1980 Variability of heart rate, P-R, QRS and Q-T durations in twins. J Electrocardiol 13 45 48

3. Newton-ChehC

GuoCY

WangTJ

O'Donnell CJ

LevyD

2007 Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study. BMC Med Genet 8 Suppl 1 S7

4. PiliaG

ChenWM

ScuteriA

OrruM

AlbaiG

2006 Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet 2 e132 doi:10.1371/journal.pgen.0020132

5. SmithJG

LoweJK

KovvaliS

MallerJB

SalitJ

2009 Genome-wide association study of electrocardiographic conduction measures in an isolated founder population: Kosrae. Heart Rhythm 6 634 641

6. HolmH

GudbjartssonDF

ArnarDO

ThorleifssonG

ThorgeirssonG

2010 Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet 42 117 122

7. HansonB

TunaN

BouchardT

HestonL

EckertE

1989 Genetic factors in the electrocardiogram and heart rate of twins reared apart and together. Am J Cardiol 63 606 9

8. PfeuferA

van NoordC

MarcianteKD

ArkingDE

LarsonMG

2010 Genome-wide association study of PR interval. Nat Genet 42 153 159

9. ChambersJC

ZhaoJ

TerraccianoCM

BezzinaCR

ZhangW

2010 Genetic variation in SCN10A influences cardiac conduction. Nat Genet 42 149 152

10. RosenbergNA

HuangL

JewettEM

SzpiechZA

JankovicI

2010 Genome-wide association studies in diverse populations. Nat Rev Genet 11 356 366

11. SolimanEZ

PrineasRJ

CaseLD

ZhangZM

GoffDCJr

2009 Ethnic distribution of ECG predictors of atrial fibrillation and its impact on understanding the ethnic distribution of ischemic stroke in the Atherosclerosis Risk in Communities (ARIC) study. Stroke 40 1204 11

12. The International HapMap Investigators 2005 A haplotype map of the human genome. Nature 437 1299 1320

13. TishkoffSA

WilliamsSM

2002 Genetic analysis of African populations: human evolution and complex disease. Nat Rev Genet 3 611 621

14. Pe'erI

YelenskyR

AltshulerD

DalyMJ

2008 Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 32 381 385

15. KoppJB

SmithMW

NelsonGW

JohnsonRC

FreedmanBI

2008 MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40 1175 1184

16. DhandapanyPS

SadayappanS

XueY

PowellGT

RaniDS

2009 A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 41 187 191

17. TishkoffSA

Reed FloydA

FriedlaenderFR

EhretC

RanciaroA

2009 The genetic structure of Africans and African Americans. Science 324 1035 44

18. SplawskiI

TimothyKW

TateyamaM

ClancyCE

MalhotraA

2002 Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 297 1333 1336

19. MusunuruK

LettreG

YoungT

FarlowDN

PirruccelloJP

2010 Candidate Gene Association Resource (CARe): Design, Methods, and Proof of Concept. Circ Cardiovasc Genet 3 267 75

20. The ARIC Investigators 1989 The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am J Epidemiol 129 687 702

21. RedlineS

TishlerPV

TostesonTD

WilliamsonJ

KumpK

1995 The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 151 682 7

22. TaylorHAJr

WilsonJG

JonesDW

SarpongDF

SrinivasanA

2005 Toward resolution of cardiovascular health disparities in African Americans: design and methods of the Jackson Heart Study. Ethn Dis 15 S6 4-17

23. BildDE

BluemkeDA

BurkeGL

DetranoR

Diez RouxAV

2002 Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol 156 871 881

24. KornJM

KuruvillaFG

McCarrollSA

WysokerA

NemeshJ

2008 Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat Genet 40 1253 1260

25. McCarrollSA

KuruvillaFG

KornJM

CawleyS

NemeshJ

2008 Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40 1166 1174

26. PurcellS

NealeB

Todd-BrownK

ThomasL

FerreiraMA

2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

27. PriceAL

PattersonNJ

PlengeRM

WeinblattME

ShadickNA

2006 Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38 904 909

28. McPeekMS

SunL

2000 Statistical tests for detection of misspecified relationships by use of genome-screen data. Am J Hum Genet 66 1076 1094

29. LiY

WillerC

SannaS

AbecasisG

2009 Genotype imputation. Annu Rev Genomics Hum Genet 10 387 406

30. KeatingBJ

TischfieldS

MurraySS

BhangaleT

PriceTS

2008 Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS ONE 3 e3583 doi:10.1371/journal.pone.0003583

31. ChenMH

YangQ

2010 GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26 580 581

32. DevlinB

RoederK

1999 Genomic control for association studies. Biometrics 55 997 1004

33. PattersonN

HattangadiN

LaneB

LohmuellerKE

HaflerDA

2004 Methods for high-density admixture mapping of disease genes. Am J Hum Genet 74 979 1000