ArticleNeurology. Genetics2022
Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants.
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Article in Neurology. Genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- Experimental models of cerebral small vessel disease: Physiological constraints, translational challenges and future directions.The Journal of physiology · 2026Review
- Late-onset dementia with leukoencephalopathy and aCerebral circulation - cognition and behavior · 2025Article
- The clinical and neuroimaging differences between vascular parkinsonism and Parkinson's disease: a case-control study.BMC neurology · 2024Article
- Enhancing the interpretation of genetic observations in KCNQ1 in unselected populations: relevance to secondary findings.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Genome mining yields putative disease-associated ROMK variants with distinct defects.PLoS genetics · 2023Article
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Authors and funding
11 authors.
Amy Christina FergusonCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
Sophie ThrippletonCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
David HenshallCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.ORCID https://orcid.org/0000-0001-7377-3969
Ed WhittakerCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.ORCID https://orcid.org/0000-0001-6394-0401
Bryan ConwayCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
Malcolm MacLeodCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.ORCID https://orcid.org/0000-0001-9187-9839
Rainer MalikCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
Konrad RawlikCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.ORCID https://orcid.org/0000-0002-0010-370X
Albert TenesaCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
Cathie SudlowCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.ORCID https://orcid.org/0000-0002-7725-7520
Kristiina RannikmaeCentre for Medical Informatics (A.C.F., D.H., A.T., K.Rannikmae), Usher Institute, University of Edinburgh; Edinburgh Medical School (S.T., E.W.), University of Edinburgh; Centre for Cardiovascular Science (B.C.), The Queen's Medical Research Institute, University of Edinburgh; Centre for Clinical Brain Sciences (M.M.), University of Edinburgh, United Kingdom; Institute for Stroke and Dementia Research (ISD) (R.M.), University Hospital, LMU Munich, Germany; The Roslin Institute (K. Rawlik, A.T.), University of Edinburgh; MRC Human Genetics Unit (A.T.), Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital; and BHF Data Science Centre (C.S.), Health Death Research UK, London, United Kingdom.
Funding
Medical Research Council MC_PC_17228Medical Research Council MC_QA137853Medical Research Council MR/S004130/1
Abstract
Background and Objectives: Based on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extracerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of putative pathogenic variants in cSVD genes in the UK Biobank (UKB), a large population-based study. Methods: We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in Results: Among UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4%-20% of variant carriers per gene had an associated phenotype. This increased to 7%-55% when including primary care records. Only Discussion: While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only approximately half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity, and/or limited statistical power.
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