<i>NOTCH3</i> variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

Cho, Bernard P.H.; Nannoni, Stefania; Harshfield, Eric L.; Tozer, Daniel J.; Gräf, Stefan; Bell, Steven; Markus, Hugh S.

doi:10.1136/jnnp-2020-325838

Cited by 52 publications

(69 citation statements)

References 36 publications

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“…We are not aware of previous studies investigating these five genes in a population-based setting. There has however been a study of another monogenic cSVD gene, which demonstrated that ∼1:450 UKB participants carry a putative pathogenic (i.e., cysteine-altering) variant NOTCH3 19 . Among the few disease-based studies exploring rare variation in cSVD genes in apparently sporadic cases, one large study found that ∼1:70 lacunar stroke patients had a monogenic cause 13 .…”

Section: Discussionmentioning

confidence: 99%

“…We found no significant interactions with sex (HTRA1 p=0.41; COL4A1 p=0.14; COL4A2 p=0.49) and ethnicity (HTRA1 p=0.60; COL4A1 p=0.88; COL4A2 p=0. 19) for any gene.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

“…We aimed to use UKB to assess the population frequency of putative pathogenic rare genetic variation in five known monogenic cSVD genes - CTSA, TREX1, HTRA1, COL4A1 and COL4A2 (excluding NOTCH3 since it has already been investigated in UKB 19 ). We studied their apparent penetrance (i.e., the proportion of participants with a variant manifesting a relevant cerebral and/or extra-cerebral clinical phenotype) and gene-phenotype associations in the general population, not selected on the basis of disease or disease risk (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data

Ferguson

Thrippleton

Henshall

et al. 2021

Preprint

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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 extra-cerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of rare variants in cSVD genes in 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 CTSA, TREX1, HTRA1, COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in UKB’s linked health data from UK hospital admissions, death records and primary care. Among 199,313 exome-sequenced UKB participants, we assessed: 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.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).While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only around 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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Section: Discussionmentioning

confidence: 99%

“…We found no significant interactions with sex (HTRA1 p=0.41; COL4A1 p=0.14; COL4A2 p=0.49) and ethnicity (HTRA1 p=0.60; COL4A1 p=0.88; COL4A2 p=0. 19) for any gene.…”

Section: (Which Was Not Certified By Peer Review) Preprintmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data

Ferguson

Thrippleton

Henshall

et al. 2021

Preprint

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“…(NOTCH3) gene, which is directly responsible for one form of VaD, and Apolipoprotein E (APOE) variants (Skoog et al, 1998;Thomas et al, 2000;Cho et al, 2021). NOTCH3 is directly linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy also known as CADASIL (Papakonstantinou et al, 2019).…”

Section: Smokingmentioning

confidence: 99%

“…Much work has been done on gene variants in AD, and the effects of these genes in VaD have been rendered. The leading players in VaD include a mutation in the Notch Receptor 3 (NOTCH3) gene, which is directly responsible for one form of VaD, and Apolipoprotein E (APOE) variants ( Skoog et al, 1998 ; Thomas et al, 2000 ; Cho et al, 2021 ). NOTCH3 is directly linked to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy also known as CADASIL ( Papakonstantinou et al, 2019 ).…”

Section: Sex-specific Differences In Vadmentioning

confidence: 99%

Vascular Dementia and Underlying Sex Differences

Akhter

Persaud

Zaokari

et al. 2021

Front. Aging Neurosci.

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Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD); where Alzheimer’s accounts for 60–70% of cases of dementia and VaD accounts for 20% of all dementia cases. VaD is defined as a reduced or lack of blood flow to the brain that causes dementia. VaD is also known occasionally as vascular contributions to cognitive impairment and dementia (VCID) or multi-infarct dementia (MID). VCID is the condition arising from stroke and other vascular brain injuries that cause significant changes to memory, thinking, and behavior, and VaD is the most severe stage while MID is produced by the synergistic effects caused by multiple mini strokes in the brain irrespective of specific location or volume. There are also subtle differences in the presentation of VaD in males and females, but they are often overlooked. Since 1672 when the first case of VaD was reported until now, sex and gender differences have had little to no research done when it comes to the umbrella term of dementia in general. This review summarizes the fundamentals of VaD followed by a focus on the differences between sex and gender when an individual is diagnosed. In addition, we provide critical evidence concerning sex and gender differences with a few of the main risk factors of VaD including pre-existing health conditions and family history, gene variants, aging, hormone fluctuations, and environmental risk factors. Additionally, the pharmaceutical treatments and possible mitigation of risk factors is explored.

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Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke

et al. 2022

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ImportanceIt 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.ObjectiveTo 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.Design, Setting, and ParticipantsThis 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 = 454 756, excluding 48 569 with incomplete data) had whole-exome sequencing and available data pertaining to lacunar stroke-related diseases, namely stroke, dementia, migraine, and epilepsy.ExposuresNOTCH3, HTRA1, and COL4A1/2 pathogenic variants in monogenic stroke; Framingham cardiovascular risk; and ischemic stroke polygenic risk.Main Outcomes and MeasuresPrimary 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.ResultsOf the 454 756 participants (208 027 [45.8%] men; mean [SD] age, 56.5 [8.1] years), 973 participants carried NOTCH3 variants, 546 carried HTRA1 variants, and 336 carried COL4A1/2 variants. Variant carriers were at least 66% more likely to have had stroke. NOTCH3 carriers had increased vascular dementia risk (OR, 5.42; 95% CI, 3.11-8.74), HTRA1 carriers an increased all-cause dementia risk (OR, 2.17; 95% CI, 1.28-3.41), and COL4A1/2 carriers an increased intracerebral hemorrhage risk (OR, 3.56; 95% CI, 1.34-7.53). NOTCH3 variants were associated with incident ischemic stroke and vascular dementia. NOTCH3 and HTRA1 variants were associated with magnetic resonance imaging markers of cSVD. Cardiovascular risk burden was associated with increased stroke risk in NOTCH3 and HTRA1 carriers. Variant location was also associated with risk.Conclusions and RelevanceIn 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.

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NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: an analysis of 200 000 participants

Cited by 52 publications

References 36 publications

Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data

Frequency and phenotype associations of rare variants in five monogenic cerebral small vessel disease genes in 200,000 UK Biobank participants with whole exome sequencing data

Vascular Dementia and Underlying Sex Differences

Association of Vascular Risk Factors and Genetic Factors With Penetrance of Variants Causing Monogenic Stroke

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