Bibi M Wolters, Mark Bakker, Kristiina Rannikmae, Paul J Hop, Ynte Ruigrok
{"title":"Rare genetic variants in PKD1 and SMAD2 are associated with intracranial aneurysms in the general population.","authors":"Bibi M Wolters, Mark Bakker, Kristiina Rannikmae, Paul J Hop, Ynte Ruigrok","doi":"10.1177/17474930251334501","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":14442,"journal":{"name":"International Journal of Stroke","volume":" ","pages":"17474930251334501"},"PeriodicalIF":6.3000,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Stroke","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/17474930251334501","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
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.
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.