心房颤动的遗传力
Heritability of Atrial Fibrillation.
作者信息
Weng Lu-Chen, Choi Seung Hoan, Klarin Derek, Smith J Gustav, Loh Po-Ru, Chaffin Mark, Roselli Carolina, Hulme Olivia L, Lunetta Kathryn L, Dupuis Josée, Benjamin Emelia J, Newton-Cheh Christopher, Kathiresan Sekar, Ellinor Patrick T, Lubitz Steven A
机构信息
From the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA (L.-C.W., S.H.C., D.K., J.G.S. P.-R.L., M.C., C.R., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.); Department of Cardiology, Clinical Sciences, Lund University, Sweden (J.G.S.); Department of Heart Failure and Valvular Disease, Skane University Hospital, Lund, Sweden (J.G.S.); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA (P.-R.L.); Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA (K.L.L., J.D., E.J.B.); Boston University School of Public Health, Boston, MA (K.L.L., J.D., E.J.B.); Boston University School of Medicine, Boston, MA (E.J.B.); and Cardiovascular Research Center (L.-C.W., D.K., J.G.S., O.L.H., C.N.-C., S.K., P.T.E., S.A.L.) and Cardiac Arrhythmia Service (P.T.E., S.A.L.), Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA.
出版信息
Circ Cardiovasc Genet. 2017 Dec;10(6). doi: 10.1161/CIRCGENETICS.117.001838.
BACKGROUND
Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified.
METHODS AND RESULTS
We assessed the contribution of genome-wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated using a variance components method with variants having a minor allele frequency ≥1%. We evaluated in age, sex, and genomic strata of interest. The for AF was 22.1% (95% confidence interval, 15.6%-28.5%) and was similar for early- versus older-onset AF (≤65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, ≥5%) variants (20.4%; 95% confidence interval, 15.1%-25.6%). Only 6.4% (95% confidence interval, 5.1%-7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions.
CONCLUSIONS
Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF.
背景
既往报告已表明多个基因位点与房颤相关，但全基因组变异对房颤易感性的影响尚未得到量化。
方法与结果
我们使用英国生物银行中120286名欧洲血统无亲属关系个体（2987例房颤患者）的数据，评估全基因组单核苷酸多态性变异对房颤风险的影响（单核苷酸多态性遗传度）。我们根据自我报告、病历计费代码、手术代码和死亡记录确定房颤。我们使用次要等位基因频率≥1%的变异，通过方差成分法估计。我们在感兴趣的年龄、性别和基因组分层中评估。房颤的为22.1%（95%置信区间为15.6%-28.5%），早发性与晚发性房颤（≤65岁与>65岁）以及男性和女性的相似。遗传变异解释的房颤变异比例主要由常见（次要等位基因频率≥5%）变异所致（20.4%；95%置信区间为15.1%-25.6%）。仅6.4%（95%置信区间为5.1%-7.7%）的房颤变异归因于已知房颤易感性、心律失常和心肌病基因区域内的变异。
结论
遗传变异对房颤风险有重大影响。基因组变异赋予的房颤风险与其他几种心血管疾病所观察到的风险相似。已确定的房颤位点仅解释了疾病风险的适度比例，这表明有必要进一步进行遗传探索，重点是常见变异，以了解房颤的因果遗传基础。
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