Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL

Background and Purpose—White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. Methods—We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. Results—Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. Conclusions—We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general

Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease

Moyamoya disease, a cerebrovascular disease leading to strokes in children and young adults, is characterized by progressive occlusion of the distal internal carotid arteries and the formation of collateral vessels. Altered genes play a prominent role in the aetiology of moyamoya disease, but a causative gene is not identified in the majority of cases. Exome sequencing data from 151 individuals from 84 unsolved families were analysed to identify further genes for moyamoya disease, then candidate genes assessed in additional cases (150 probands). Two families had the same rare variant in ANO1, which encodes a calcium-activated chloride channel, anoctamin-1. Haplotype analyses found the families were related, and ANO1 p.Met658Val segregated with moyamoya disease in the family with an LOD score of 3.3. Six additional ANO1 rare variants were identified in moyamoya disease families. The ANO1 rare variants were assessed using patch-clamp recordings, and the majority of variants, including ANO1 p.Met658Val, displayed increased sensitivity to intracellular Ca2+. Patients harbouring these gain-of-function ANO1 variants had classic features of moyamoya disease, but also had aneurysm, stenosis and/or occlusion in the posterior circulation. Our studies support that ANO1 gain-of-function pathogenic variants predispose to moyamoya disease and are associated with unique involvement of the posterior circulation

Research Progresses in Understanding the Pathophysiology of Moyamoya Disease

Background: The pathogenesis of moyamoya disease (MMD) is still unknown. The detection of inflammatory molecules such as cytokines, chemokines and growth factors in MMD patients' biological fluids supports the hypothesis that an abnormal angiogenesis is implicated in MMD pathogenesis. However, it is unclear whether these anomalies are the consequences of the disease or rather causal factors as well as these mechanisms remain insufficient to explain the pathophysiology of MMD. The presence of a family history in about 9-15% of Asian patients, the highly variable incidence rate between different ethnic and sex groups and the age of onset support the role of genetic factors in MMD pathogenesis. However, although some genetic loci have been associated with MMD, few of them have been replicated in independent series. Recently, RNF213 gene was shown to be strongly associated with MMD occurrence with a founder effect in East Asian patients. However, the mechanisms leading from RNF213 mutations to MMD clinical features are still unknown. Summary: The research on pathogenic mechanism of MMD is in its infancy. MMD is probably a complex and heterogeneous disorder, including different phenotypes and genotypes, in which more than a single factor is implicated. Key Message: Since the diagnosis of MMD is rapidly increasing worldwide, the development of more efficient stratifying risk systems, including both clinical but also biological drivers became imperative to improve our ability of predict prognosis and to develop mechanism-tailored interventions. (C) 2016 S. Karger AG, BaselPeer reviewe

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate

Funding Information: This project is an EU Joint Programme Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organisations under the aegis of JPND www.jpnd. eu: Australia, National Health and Medical Research Council, Austria, Federal Ministry of Science, Research and Economy; Canada, Canadian Institutes of Health Research; France, French National Research Agency; Germany, Federal Ministry of Education and Research; Netherlands, The Netherlands Organization for Health Research and Development; United Kingdom, Medical Research Council. This project has received funding from the European Union s Horizon 2020 research and innovation programme under grant agreement No 643417. This project has also received funding from the European Research Council (ERC) under the European Union s Horizon 2020 research and innovation programme under grant agreement No. 640643 and from the European Union s Horizon 2020 research and innovation programme under grant agreements Nos. 667375 and 754517. This work was also supported by a grant overseen by the French National Research Agency (ANR) as part of ANR-14-CE12-60016 and the Investment for the Future Programme ANR-18-RHUS-0002. Part of the computations were performed at the Bordeaux Bioinformatics Centre (CBiB), University of Bordeaux and at the CREDIM (Centre de Ressource et Dffeveloppement en Informatique Medicale) at University of Bordeaux, on a server infrastructure supported by the Fondation Claude Pompidou. The neurology Working Group in the CHARGE Consortium is partly funded by the CHARGE infrastructure grant R01HL105756 and grants from the National Institute on Aging, AG033193, AG049505, AG052409 and AG059421. P.M.M. acknowledges personal support from the Edmond J Safra Foundation and Lily Safra and an NIHR Senior Investigator Award and research support from the UK Dementia Research Institute and NIHR Imperial College Healthcare Trust Biomedical Research Centre. Study-specific funding information is provided in the Supplementary material. Publisher Copyright: © 2022 The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41326), whole-exome sequencing (n = 15965), or exome chip (n = 5249) data contributed 13776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5′ UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.Peer reviewe

Bases moléculaires et mécanismes physiopathogéniques de CADASIL : un modèle de maladie des petites artères cérébrales

Les maladies des petites artères cérébrales sont la cause d’environ 20 % des accidents ischémiques cérébraux. Leur diagnostic est difficile et leurs mécanismes physiopathogéniques très obscurs. Un certain nombre de ces artériopathies sont familiales. A la fin des années 80, une forme autosomique dominante d’artériopathie cérébrale, CADASIL, se manifestant par des accidents ischémiques cérébraux récurrents, des troubles cognitifs et une atteinte sévère de la substance blanche a été identifiée dans un très petit nombre de familles. Nous avons établi qu’un gène de la famille très conservée des récepteurs Notch impliqués dans les processus de différenciation et de prolifération cellulaire au cours du développement, Notch3, était le gène responsable de CADASIL. À ce jour, plus de 300 familles ont été étudiées et, récemment, des cas sporadiques liés à une néomutation ont été identifiés, suggérant que CADASIL n’est probablement pas une cause rare d’artériopathie cérébrale. On ne connaît pas encore le rôle exact de Notch3. Nous avons récemment montré que, chez l’homme adulte, l’expression de Notch3 est restreinte aux vaisseaux et à la cellule musculaire lisse. Par ailleurs, nous avons établi que, chez les patients CADASIL, il existe une anomalie de la clairance de Notch3 entraînant son accumulation à la membrane cytoplasmique des cellules musculaires lisses vasculaires. Les résultats de ces travaux indiquent donc que la cellule musculaire lisse vasculaire est la cible primaire du processus pathogène de CADASIL. Par ailleurs ils suggèrent fortement que la voie de signalisation Notch3 est impliquée dans l’homéostasie du vaisseau adulte. Enfin ces travaux ouvrent de nouvelles perspectives dans le domaine de la pathologie neurovasculaire. En particulier la mise au point d’un test diagnostique de CADASIL fiable et faisable en routine permettra prochainement de déterminer la prévalence de cette affection, 1ère étape dans le démembrement des maladies des petites artères cérébrales, affections pour lesquelles les partenaires de Notch3 sont autant de candidats potentiels