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

Ferguson, Amy; Thrippleton, Sophie; Henshall, David; Whittaker, Ed; Conway, Bryan; Macleod, Malcolm; Malik, Rainer; Rawlik, Konrad; Tenesa, Albert; Sudlow, Cathie; Rannikmäe, Kristiina

doi:10.1212/nxg.0000000000200015

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…In more than 450 000 individuals, we demonstrated that NOTCH3, HTRA1, and COL4A1/2 variants identical to those causing monogenic cSVD are much more frequent than expected in the general population based on the frequency of clinical disease caused by these variants. This is consistent with reports from various population databases, 5,6,36,37 demonstrating that such variants occur in 2 to 3 individuals per 1000. Our results extend previous work by showing association of such variants with disease.…”

Section: Discussionsupporting

confidence: 92%

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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Section: Discussionsupporting

confidence: 92%

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

et al. 2022

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“…Earlier work in smaller cohorts (predominantly focused on NOTCH3 ) suggest that pathogenic variants are more frequent than expected based on prevalence of disease phenotype . Some studies identify differences in penetrance, expressivity, and a globally increased risk of stroke and/or vascular dementia . Cho et al reported consistent findings: pathogenic variants in all 3 genes were markedly more frequent than expected based on prevalence of clinical disease phenotypes thought to be caused by these variants.…”

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confidence: 87%

“…The results are balanced between confirmatory vs novel/hypothesis generating. In all 3 genes, the study supports previous data of lower penetrance rates and overestimated variant pathogenicity . A significant proportion of asymptomatic carriers were identified when evaluating for prevalence and incidence of cSVD (median follow-up, 12.6 years).…”

mentioning

confidence: 92%

“…C OL4A1/2 encodes a type IV collagen α protein expressed in basement membranes of blood vessels with pathogenic variants resulting in lacunar stroke or intracerebral hemorrhage. Earlier work in smaller cohorts (predominantly focused on NOTCH3 ) suggest that pathogenic variants are more frequent than expected based on prevalence of disease phenotype . Some studies identify differences in penetrance, expressivity, and a globally increased risk of stroke and/or vascular dementia .…”

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confidence: 93%

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Monogenic Stroke—Can We Overcome Nature With Nurture?

Jha

2022

JAMA Neurol

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Although genetic underpinnings of several neurological disorders like epilepsy have been described as early as fourth century BCE in the Corpus Hippocraticum, 1 discoveries in stroke have been more recent. One of the first reports demonstrating the importance of heredity in stroke pathogenesis occurred in 1974 with the generation of the stroke-prone spontaneously hypertensive rat. 2 This strain was created using selective breeding and has endured as a valuable asset in contemporary stroke research. Nonetheless, half a century later, the precise genetic determinants even in this single, highly specific rodent stroke phenotype have not been completely elucidated despite immense advances in next-generation sequencing and genome mapping. 3,4 In humans, the role of genetics in stroke is exponentially more complex. Stroke is heterogeneous, as are its predisposing risk factors, which also have their own genetic contributors. Genetics may either mediate or moderate stroke via multiple mechanisms. Genome-wide association studies since 2007 have identified several common loci and variants that typically account for a small proportion of the heritable risk of stroke, stroke subtypes, or conventional stroke risk factors. 5 Monogenic stroke has classically resided on the other end of the continuum, where rare variants in a single gene are often thought to cause diseases. Here, the genetic alteration may contribute to inherited syndromes where stroke is the primary phenotype (eg, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]), or multisystem disorders that include stroke as a manifestation (eg, sickle cell anemia). 6 The causative paradigm in monogenic stroke has evolved over the past decade with increasing recognition of variability in penetrance, expressivity, and potential for modulation by risk factors and other genes. [7][8][9][10]

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“…Despite the reported cases of parkinsonism-related genetic leukoencephalopathy, these cases represent a small percentage of patients with cerebral small vessel disease, with overlapped clinical features and neuroimaging [ 66 , 67 ], indicating the need for genetic testing of patients’ cohorts to confirm its frequency among patients diagnosed currently with VaP. Most cerebral small vessel disease cases are attributed to interaction between environmental factors and multiple genetic variants, while monogenic variants represent a minor percentage (up to 5%) [ 67 , 68 ].…”

Section: Discussionmentioning

confidence: 99%

The clinical and neuroimaging differences between vascular parkinsonism and Parkinson’s disease: a case-control study

George,

Roushdy,

Fathy

et al. 2024

BMC Neurol

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Background Parkinson’s disease (PD) and vascular parkinsonism (VaP) have highly overlapping phenotypes, and different prognosis. This study comprehensively investigated the clinical, brain MRI and transcranial sonography differences between VaP and PD. Methods Forty-eight patients with PD, 27 patients with VaP, and 29 healthy controls were compared. All patients were assessed using the MDS-UPDRS, Berg Balance Scale (BBS), Ten-Meter Walking Test (10-MWT), Time Up and Go Test, and Non-Motor Symptoms Scale. Beck Depression Inventory, PD questionnaire- 39, international urine incontinence scale, cognitive assessment scales, MRI brain and transcranial colour-coded doppler. The study was registered on clinical-Trial.gov (NCT04308135) on 03/12/2020. Results VaP patients showed significantly older age of onset, shorter disease duration, lower drug doses and levodopa responsiveness, higher On and Off axial scores, On and Off BBS, higher On scores for PIGD, rigidity, bradykinesia and total motor MDS-UPDRS, lower On and Off tremor, lower-half predominance, lower asymmetrical presentation and symmetric index than PD patients. VaP patients had worse non-motor symptoms Scale (NMSS) than controls except for perceptual problems/hallucinations but better symptoms than PD patients except for urinary dysfunction. Quality of life (QoL) was impaired in VaP patients and was correlated with motor function and NMSs. The VaP group had significantly higher white matter lesions and brain atrophy, with lower hyperechogenicity of the substantia nigra and more impaired cerebral vascular resistance and vasoreactivity than the PD group. Conclusions VaP has a characteristic motor and non-motor profile, with impaired QoL, white matter, and transcranial sonography abnormalities that differentiate it from PD. Further studies are warranted to explore the role of vascular lesions in the pathogenesis of VaP. Trial registration The registered identifier NCT04308135 on clinical-Trial.gov. Registered on 03/12/2020.

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

Cited by 9 publications

References 34 publications

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

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

Monogenic Stroke—Can We Overcome Nature With Nurture?

The clinical and neuroimaging differences between vascular parkinsonism and Parkinson’s disease: a case-control study

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