{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T08:39:57Z","timestamp":1792485597419,"version":"4.5.0"},"reference-count":39,"publisher":"American Medical Association (AMA)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"\n Importance<\/jats:title>\n It is uncertain whether typical variants causing monogenic stroke are associated with cerebrovascular disease in the general population and why the phenotype of these variants varies so widely.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine the frequency of pathogenic variants in the 3 most common monogenic cerebral small vessel diseases (cSVD) and their associations with prevalent and incident stroke and dementia.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study is a multicenter population-based study of data from UK Biobank participants recruited in 2006 through 2010, with the latest follow-up in September 2021. A total of 9.2 million individuals aged 40 to 69 years who lived in the United Kingdom were invited to join UK Biobank, of whom 5.5% participated in the baseline assessment. Participants eligible for our study (n\u2009=\u2009454\u202f756, excluding 48\u202f569 with incomplete data) had whole-exome sequencing and available data pertaining to lacunar stroke-related diseases, namely stroke, dementia, migraine, and epilepsy.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n NOTCH3, HTRA1<\/jats:italic>\n , and\n COL4A1\/2<\/jats:italic>\n pathogenic variants in monogenic stroke; Framingham cardiovascular risk; and ischemic stroke polygenic risk.\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Primary outcomes were prevalent and incident stroke and dementia. Odds ratios (ORs) and hazard ratios (HRs) were adjusted for age, sex, ethnicity, exome sequencing batch, and top 10 genetic principal components.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of the 454\u202f756 participants (208\u202f027 [45.8%] men; mean [SD] age, 56.5 [8.1] years), 973 participants carried\n NOTCH3<\/jats:italic>\n variants, 546 carried\n HTRA1<\/jats:italic>\n variants, and 336 carried\n COL4A1\/2<\/jats:italic>\n variants. Variant carriers were at least 66% more likely to have had stroke.\n NOTCH3<\/jats:italic>\n carriers had increased vascular dementia risk (OR, 5.42; 95% CI, 3.11-8.74),\n HTRA1<\/jats:italic>\n carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41), and\n COL4A1\/2<\/jats:italic>\n carriers an increased intracerebral hemorrhage risk (OR, 3.56; 95% CI, 1.34-7.53).\n NOTCH3<\/jats:italic>\n variants were associated with incident ischemic stroke and vascular dementia.\n NOTCH3<\/jats:italic>\n and\n HTRA1<\/jats:italic>\n variants were associated with magnetic resonance imaging markers of cSVD. Cardiovascular risk burden was associated with increased stroke risk in\n NOTCH3<\/jats:italic>\n and\n HTRA1<\/jats:italic>\n carriers. Variant location was also associated with risk.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this cohort study, pathogenic variants associated with rare monogenic stroke were more common than expected in the general population and associated with stroke and dementia. Cardiovascular risk burden is associated with the penetrance of such variants. Our results support the hypothesis that cardiovascular risk factor control may improve disease prognosis in individuals with monogenic cSVD variants. This lays the foundation for future studies to evaluate the effect of early identification before symptom onset on mitigating stroke and dementia risk.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2022.3832","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T04:30:38Z","timestamp":1666845038000},"page":"1303","source":"Crossref","is-referenced-by-count":64,"title":["Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke"],"prefix":"10.1001","volume":"79","author":[{"given":"Bernard P. 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