与晕厥相关的基因变异涉及神经和自主神经过程。

Genetic variants associated with syncope implicate neural and autonomic processes.

作者信息

Aegisdottir Hildur M, Thorolfsdottir Rosa B, Sveinbjornsson Gardar, Stefansson Olafur A, Gunnarsson Bjarni, Tragante Vinicius, Thorleifsson Gudmar, Stefansdottir Lilja, Thorgeirsson Thorgeir E, Ferkingstad Egil, Sulem Patrick, Norddahl Gudmundur, Rutsdottir Gudrun, Banasik Karina, Christensen Alex Hoerby, Mikkelsen Christina, Pedersen Ole Birger, Brunak Søren, Bruun Mie Topholm, Erikstrup Christian, Jacobsen Rikke Louise, Nielsen Kaspar Rene, Sørensen Erik, Frigge Michael L, Hjorleifsson Kristjan E, Ivarsdottir Erna V, Helgadottir Anna, Gretarsdottir Solveig, Steinthorsdottir Valgerdur, Oddsson Asmundur, Eggertsson Hannes P, Halldorsson Gisli H, Jones David A, Anderson Jeffrey L, Knowlton Kirk U, Nadauld Lincoln D, Haraldsson Magnus, Thorgeirsson Gudmundur, Bundgaard Henning, Arnar David O, Thorsteinsdottir Unnur, Gudbjartsson Daniel F, Ostrowski Sisse R, Holm Hilma, Stefansson Kari

机构信息

deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.

Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik 101, Iceland.

出版信息

Eur Heart J. 2023 Mar 21;44(12):1070-1080. doi: 10.1093/eurheartj/ehad016.

DOI:10.1093/eurheartj/ehad016

PMID:36747475

Abstract

AIMS

Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications.

METHODS AND RESULTS

This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders.

CONCLUSION

The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

摘要

目的

晕厥是一种常见且在临床上具有挑战性的病症。在本研究中，对晕厥的遗传学进行了调查，以探寻其病理生理学及预后意义方面的知识。

方法与结果

这项全基因组关联荟萃分析纳入了来自 deCODE 遗传学公司（冰岛）、英国生物银行（英国）以及哥本哈根医院生物银行心血管研究/丹麦献血者研究（丹麦）的 56071 例晕厥病例和 890790 例对照，并对来自美国犹他州山间医疗中心和芬兰 FinnGen 的 22412 例病例和 286003 例对照的变异进行了随访评估。该研究产生了 18 个独立的晕厥变异，其中 17 个是新发现的。其中一个变异，即 PTPRN2 的 p.Ser140Thr，仅在母系遗传时影响晕厥。另一个变异与献血期间的血管迷走反应相关，还有五个与心率和/或血压调节相关，其影响方向各不相同。这 18 个关联均不能归因于心血管疾病或其他疾病。关于调控元件的注释表明，晕厥变异优先位于神经特异性调控区域。孟德尔随机化分析支持冠状动脉疾病对晕厥有因果效应。晕厥的多基因评分（PGS）捕捉到了与心血管疾病、糖尿病、抑郁症及寿命缩短的遗传相关性。然而，仅基于这 18 个晕厥变异的评分在检测晕厥风险方面与 PGS 表现相似，但与其他疾病无关。