Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants.

Journal

Neurology. Genetics
ISSN: 2376-7839
Titre abrégé: Neurol Genet
Pays: United States
ID NLM: 101671068

Informations de publication

Date de publication:
Oct 2022
Historique:
received: 24 02 2022
accepted: 17 06 2022
entrez: 29 8 2022
pubmed: 30 8 2022
medline: 30 8 2022
Statut: epublish

Résumé

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. We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in 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 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.

Sections du résumé

Background and Objectives UNASSIGNED
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 UNASSIGNED
We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in
Results UNASSIGNED
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 UNASSIGNED
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.

Identifiants

DOI: 10.1212/NXG.0000000000200015 PMID: 36035235 PMC: PMC9403885
pubmed: 36035235
doi: 10.1212/NXG.0000000000200015
pii: NNG-2022-200018
pmc: PMC9403885
doi:

Types de publication

Journal Article

Langues

eng

Pagination

e200015

Informations de copyright

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Amy Christina Ferguson (AC)

Centre 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 Thrippleton (S)

Centre 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 Henshall (D)

Centre 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: 0000-0001-7377-3969

Ed Whittaker (E)

Centre 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: 0000-0001-6394-0401

Bryan Conway (B)

Centre 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 MacLeod (M)

Centre 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: 0000-0001-9187-9839

Rainer Malik (R)

Centre 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 Rawlik (K)

Centre 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: 0000-0002-0010-370X

Albert Tenesa (A)

Centre 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 Sudlow (C)

Centre 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: 0000-0002-7725-7520

Kristiina Rannikmae (K)

Centre 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.

Classifications MeSH