Genome-wide association studies of the PR interval in African Americans.
Genome-wide association studies of the PR interval in African Americans.
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DOI：
10.1371/journal.pgen.1001304
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发表时间：
2011-02-10
期刊：
影响因子：
4.5
通讯作者：
Candidate-gene Association Resource (CARe) Consortium
中科院分区：
文献类型：
--
作者：
Smith JG;Magnani JW;Palmer C;Meng YA;Soliman EZ;Musani SK;Kerr KF;Schnabel RB;Lubitz SA;Sotoodehnia N;Redline S;Pfeufer A;Müller M;Evans DS;Nalls MA;Liu Y;Newman AB;Zonderman AB;Evans MK;Deo R;Ellinor PT;Paltoo DN;Newton-Cheh C;Benjamin EJ;Mehra R;Alonso A;Heckbert SR;Fox ER;Candidate-gene Association Resource (CARe) Consortium
心电图上的PR间期反映了房室结传导时间。PR间期是可遗传的，提供了有关心律失常风险的重要信息，并被认为在人类之间存在差异。全基因组关联(GWA)研究已经在欧洲和亚洲血统的个体中发现了PR间隔的共同遗传决定因素，但在非洲血统的个体中普遍缺乏GWA研究。我们对来自四个队列(n = 6,247)的非裔美国人进行了GWA研究，以确定与PR间期持续时间相关的遗传变异。采用Affymetrix 6.0基因芯片进行基因分型。使用YRI和CEU组合的HapMap II期面板对280万个单核苷酸多态(SNPs)进行归因。在四个队列中的两个和荟萃分析中，我们观察到编码心脏钠通道(SCN5A)的基因中有一个强信号(Rs3922844)与全基因组显著相关(p<；2.5×10−8)。该信号解释了非裔美国人PR间期变异性的2%(每个次要等位基因的β = 为5.1毫秒，95%CI = 4.16.1，p = 3×10−23)。在欧洲血统个体(n = 14,042)中，该SNP还与PR间期(每个小等位基因β = 2.4ms，95%CI 1.83.0，p = 3×10−16)相关，但效应大小较小(p为异质性和lt；0.001)和可解释的变异性(0.5%)。进一步的荟萃分析发现，在全基因组范围内，SCN10A(Rs6798015)、MEIS1(Rs10865355)和TBX5(Rs7312625)中的SNPs与欧洲和亚洲GWA研究中发现的SNPs高度相关。在一个队列中，非洲血统与PR持续时间(13.3ms，p = 0.009)有关，而在另外三个队列中，非洲血统与PR持续时间无关。我们的发现证明了在欧洲和亚洲样本中与PR间期相关的四个座位上的常见变异与非裔美国人的相关性，并在其中一个座位上发现了与PR间期相关的关联信号，在非裔美国人中比在欧洲人中更强。我们对来自四个基于人群的队列的非裔美国人参与者进行了全基因组关联研究，以确定与PR间期时程变化相关的遗传变异，PR间期时程是通过心房和房室结传导的心电图指标。我们在两个队列和四个非裔美国人队列的荟萃分析中观察到编码心脏钠通道的基因SCN5A与全基因组显著关联(p<；2.5×10−8)的强烈信号。我们在另外两个非裔美国人和欧洲人中复制了这种关联(p = 3×10−16)。这一信号解释了非裔美国人2%的公关持续时间变异性和欧洲人0.5%的公关持续时间变异性。在进一步的荟萃分析中，我们观察到SCN10A、MEIS1、TBX5的单核苷酸多态在全基因组范围内的显著相关性，对应于在欧洲和亚洲后裔中观察到的信号。我们在一个队列中发现了遗传祖先和PR间期的关联，但在另外三个队列中没有发现。我们的发现首次证明了这些基因座与非洲血统个体的相关性，并确定了来自SCN5A的关联信号，该信号与非裔美国人的PR间隔更密切相关。
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. We performed genome-wide association studies in African American participants from four population-based cohorts to identify genetic variation that correlates with variation in PR interval duration, an electrocardiographic measure of conduction through the atria and atrioventricular node. We observed a strong signal within the gene encoding the cardiac sodium channel, SCN5A, with genome-wide significant association (p<2.5×10−8) in two cohorts and in a meta-analysis of four cohorts with African Americans. We replicated this association in two additional cohorts of African Americans and in Europeans (p = 3×10−16). The signal explains 2% of PR duration variability in African Americans and 0.5% in Europeans. In further meta-analysis, we observed genome-wide significant associations for single nucleotide polymorphisms in SCN10A, MEIS1, TBX5, corresponding to signals observed in people of European and Asian descent. We found an association of genetic ancestry and PR interval in one but not the other three cohorts. Our findings provide the first demonstration of the relevance of these loci to individuals of African ancestry and identify an association signal from SCN5A that is more strongly associated with PR interval in African Americans.
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影响因子：
30.8
作者：
Kopp, Jeffrey B.;Smith, Michael W.;Nelson, George W.;Johnson, Randall C.;Freedman, Barry I.;Bowden, Donald W.;Oleksyk, Taras;McKenzie, Louise M.;Kajiyama, Hiroshi;Ahuja, Tejinder S.;Berns, Jeffrey S.;Briggs, William;Cho, Monique E.;Dart, Richard A.;Kimmel, Paul L.;Korbet, Stephen M.;Michel, Donna M.;Mokrzycki, Michele H.;Schelling, Jeffrey R.;Simon, Eric;Trachtman, Howard;Vlahov, David;Winkler, Cheryl A.
通讯作者：
Winkler, Cheryl A.
影响因子：
2.8
作者：
HANSON, B;TUNA, N;RICH, S
通讯作者：
RICH, S
影响因子：
1.3
作者：
HAVLIK, RJ;GARRISON, RJ;FEINLEIB, M
通讯作者：
FEINLEIB, M
影响因子：
30.8
作者：
通讯作者：
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DOI：
10.1161/circgenetics.109.882696
发表时间：
2010-06
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Musunuru K;Lettre G;Young T;Farlow DN;Pirruccello JP;Ejebe KG;Keating BJ;Yang Q;Chen MH;Lapchyk N;Crenshaw A;Ziaugra L;Rachupka A;Benjamin EJ;Cupples LA;Fornage M;Fox ER;Heckbert SR;Hirschhorn JN;Newton-Cheh C;Nizzari MM;Paltoo DN;Papanicolaou GJ;Patel SR;Psaty BM;Rader DJ;Redline S;Rich SS;Rotter JI;Taylor HA Jr;Tracy RP;Vasan RS;Wilson JG;Kathiresan S;Fabsitz RR;Boerwinkle E;Gabriel SB;NHLBI Candidate Gene Association Resource
通讯作者：
NHLBI Candidate Gene Association Resource