| Title: | Frequency and Phenotype Associations of Rare Variants in 5 Monogenic Cerebral Small Vessel Disease Genes in 200,000 UK Biobank Participants |
| Journal: | Neurology Genetics |
| Published: | 24 Aug 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36035235/ |
| DOI: | https://doi.org/10.1212/nxg.0000000000200015 |
| URL: | https://ng.neurology.org/content/nng/8/5/e200015.full.pdf |
Publication 14134
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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.</p>
Methods: We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA, TREX1, HTRA1, and COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in the UKB's linked health data from UK hospital admissions, death records, and primary care. Among 199,313 exome-sequenced UKB participants, we assessed the following: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach.</p>
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 COL4A1 variant carrier status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR = 1.29, p = 0.006).</p>
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.</p>
11 Authors
- Amy Christina Ferguson
- Sophie Thrippleton
- David Henshall
- Ed Whittaker
- Bryan Conway
- Malcolm MacLeod
- Rainer Malik
- Konrad Rawlik
- Albert Tenesa
- Cathie Sudlow
- Kristiina Rannikmae
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