Frequency and phenotype associations of rare variants in 5 monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants

Amy Ferguson, Sophie Thrippleton, David E Henshall , Ed Whittaker, Bryan Ronald Conway, Malcolm MacLeod, Rainer Malik, Konrad Rawlik, Albert Tenesa, Cathie L M Sudlow, Kristiina Rannikmae

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 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.

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).

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.

Original languageEnglish
Article numbere200015
Pages (from-to)e200015
JournalNeurology Genetics
Issue number5
Early online date24 Aug 2022
Publication statusPublished - 1 Oct 2022


Dive into the research topics of 'Frequency and phenotype associations of rare variants in 5 monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants'. Together they form a unique fingerprint.

Cite this