Rare genetic variants in PKD1 and SMAD2 are associated with intracranial aneurysms in the general population.

IF 6.3 2区 医学 Q1 CLINICAL NEUROLOGY
Bibi M Wolters, Mark Bakker, Kristiina Rannikmae, Paul J Hop, Ynte Ruigrok
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引用次数: 0

Abstract

IntroductionFamily studies identified several rare genetic risk variants for intracranial aneurysms (IA) and aneurysmal subarachnoid hemorrhage (ASAH). Additionally, certain monogenic disorders caused by rare penetrant genetic variants predispose individuals to IA and ASAH. We investigated the effect of these variants on IA and ASAH in the general population.Patients and MethodsWe tested the association between genetic variants within IA-associated genes and IA and ASAH using a burden test, sequence kernel association test (SKAT), and variant-level aggregated Cauchy association test (ACAT-V) in the UK Biobank. Variants were stratified by allele frequency and predicted impact on the protein structure. Sensitivity analyses were performed on only ASAH patients and excluding participants diagnosed with an aforementioned monogenic disorder.ResultsIn the group of 1,656 IA cases, including 928 ASAH cases, and 391,948 controls, associations were identified for ultrarare variants with moderate or high impact in PKD1 (odds ratio [OR]=1.42; 95% confidence interval [95%CI]=1.06-1.85, p=4.28×10-7 [SKAT]) and SMAD2 (OR=4.89; 95%CI=1.63-11.05, p=7.10×10-5 [SKAT]). Upon excluding participants diagnosed with the respective monogenic disorders, these associations remained. When considering only ASAH cases, the association with SMAD2 was similar (OR=4.85; 95%CI=1.02-13.7; p=9.0×10-4) while for PKD1 the association diminished (OR=1.29; 95%CI=0.85-1.87; p=0.043).Discussion and ConclusionUltrarare damaging variants in PKD1, a gene causing autosomal dominant polycystic kidney disease, and SMAD2, a gene causing Loeys-Dietz syndrome, were associated with IA in the general population, even in the absence of a diagnosis of these disorders. Our results may contribute to the development of genetic screening methods for IA in a clinical setting.

在普通人群中,PKD1和SMAD2的罕见遗传变异与颅内动脉瘤有关。
家族研究发现了颅内动脉瘤(IA)和动脉瘤性蛛网膜下腔出血(ASAH)的几种罕见遗传风险变异。此外,某些由罕见的渗透性遗传变异引起的单基因疾病使个体易患IA和ASAH。我们调查了这些变异对普通人群中IA和ASAH的影响。患者和方法我们使用英国生物银行的负担试验、序列核关联试验(SKAT)和变异水平聚集柯西关联试验(ACAT-V)检测IA相关基因的遗传变异与IA和ASAH之间的关系。根据等位基因频率对变异进行分层,并预测对蛋白质结构的影响。敏感性分析仅对ASAH患者进行,排除了诊断为上述单基因疾病的参与者。结果在1,656例IA病例(包括928例ASAH病例)和391,948例对照中,发现与PKD1中度或高度影响的超罕见变异相关(优势比[or]=1.42;95%置信区间[95% ci]=1.06-1.85, p=4.28×10-7 [SKAT])和SMAD2 (OR=4.89;95%CI=1.63 ~ 11.05, p=7.10×10-5 [SKAT])。在排除被诊断为各自单基因疾病的参与者后,这些关联仍然存在。当仅考虑ASAH病例时,与SMAD2的相关性相似(OR=4.85;95%可信区间= 1.02 - -13.7;p=9.0×10-4),而PKD1的相关性减弱(OR=1.29;95%可信区间= 0.85 - -1.87;p = 0.043)。讨论与结论:在普通人群中,即使没有诊断出这些疾病,也存在导致常染色体显性多囊肾病的基因PKD1和导致Loeys-Dietz综合征的基因SMAD2的罕见破坏性变异与IA相关。我们的结果可能有助于在临床环境中发展IA的遗传筛查方法。
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来源期刊
International Journal of Stroke
International Journal of Stroke 医学-外周血管病
CiteScore
13.90
自引率
6.00%
发文量
132
审稿时长
6-12 weeks
期刊介绍: The International Journal of Stroke is a welcome addition to the international stroke journal landscape in that it concentrates on the clinical aspects of stroke with basic science contributions in areas of clinical interest. Reviews of current topics are broadly based to encompass not only recent advances of global interest but also those which may be more important in certain regions and the journal regularly features items of news interest from all parts of the world. To facilitate the international nature of the journal, our Associate Editors from Europe, Asia, North America and South America coordinate segments of the journal.
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