A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
A comprehensive evaluation of the genetic architecture of sudden cardiac arrest
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DOI：
10.1093/eurheartj/ehy474
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发表时间：
2018-11-21
影响因子：
39.3
通讯作者：
Sotoodehnia, Nona
中科院分区：
文献类型：
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作者：
Ashar, Foram N.;Mitchell, Rebecca N.;Sotoodehnia, Nona
心脏骤停（SCA）占西方人群成人死亡率的10%。我们的目的是确定潜在的位点与SCA，并确定与SCA.Methods和结果有因果关系的危险因素，我们进行了一个大的全基因组关联研究（GWAS）SCA（n = 3939例，25 989非病例），以检查常见的变异全基因组和候选心律失常基因。我们还利用孟德尔随机化（MR）方法，使用跨性状多变异遗传风险评分关联（GRSA）来评估18个危险因素与SCA的因果关系。没有变异与SCA在全基因组的显着性，也没有共同的候选心律失常基因变异与SCA在名义上的显着性。使用交叉性状GRSA，我们建立了SCA与（i）冠状动脉疾病（CAD）和传统CAD危险因素之间的遗传相关性（血压、血脂和糖尿病），（ii）身高和BMI，以及（iii）电不稳定性特征（QT和房颤），结论我们的研究结果表明，对SCA的遗传结构进行全面的研究，阐明了一般人群中具有多种影响因素的复杂危及生命的疾病的决定因素。这种遗传分析的结果，无论是积极的还是消极的发现，都对评估有SCA家族史的患者的遗传结构，以及在高危人群和一般社区预防SCA的努力有影响。
Aims Sudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. We aim to identify potential loci associated with SCA and to identify risk factors causally associated with SCA.Methods and results We carried out a large genome-wide association study (GWAS) for SCA (n = 3939 cases, 25 989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization (MR) methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA. No variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (i) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (ii) height and BMI, and (iii) electrical instability traits (QT and atrial fibrillation), suggesting aetiologic roles for these traits in SCA risk.Conclusions Our findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in high-risk populations and the general community.