Migraine, Stroke, and Cervical Arterial Dissection Shared Genetics for a Triad of Brain Disorders With Vascular Involvement

Background and Objectives Migraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Larger samples and recent advances in methodology invite systematic exploration of their shared genetics. Methods Genetic analyses leveraged summary statistics from genome-wide association studies of the largest available samples of each disorder, including subtypes of stroke (ischemic stroke, large artery stroke, small vessel stroke, and cardioembolic stroke) and migraine (with aura and without aura). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within independent segments across the genome including known specific loci for each disorder. A cross-trait meta-analysis was used to identify novel candidate loci. Finally, potential causality of migraine susceptibility on stroke and CeAD was assessed by Mendelian randomization. Results Among all pairs of disorders, genome-wide genetic correlation was observed only between CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than those between migraine and stroke or CeAD and stroke and revealed evidence for novel CeAD associations at rs6693567 (ADAMTSL4/ECM1), rs11187838 (PLCE1), and rs7940646 (MRVI1) while strengthening prior subthreshold evidence at rs9486725 (FHLS) and rs650724 (LRP1). At known migraine loci, novel associations with stroke had concordant risk alleles for small vessel stroke at rs191602009 (CARP) and for cardioembolic stroke at rs55884259 (NKX2-5). Known migraine loci also revealed novel associations but with opposite risk alleles for all stroke, ischemic stroke, and small vessel stroke at rs55928386 (HTRA1), for large artery stroke at rs11172113 (LRP1), and for all stroke and ischemic stroke at rs1535791 and rs4942561 (both LRCH1), respectively. rs182923402 (near PTCH1) was a novel concordant locus for migraine and cardioembolic stroke. Mendelian randomization supported potential causal influences of migraine on CeAD (odds ratio [95% confidence interval] per doubling migraine prevalence = 1.69 [1.24-2.3], p = 0.0009) with concordant risk, but with opposite risk on large artery stroke (0.86 [0.76-0.96], p = 0.0067). Discussion The findings emphasize shared genetic risk between migraine and CeAD while identifying loci with likely vascular function in migraine and shared but opposite genetic risk between migraine and stroke subtypes, and a central role of LRP1 in all 3 cerebrovascular disorders.Peer reviewe

Genome-Wide Meta-analysis identifies three novel loci associated with stroke

We conducted a European‐only and transancestral genome‐wide association meta‐analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E‐8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04–1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E‐8, OR = 1.04, 95% CI = 1.03–1.06) and near DYRK1A (rs720470; p = 6.1E‐9, OR = 1.05, 95% CI = 1.03–1.07) at genome‐wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase–nitric oxide pathway in part affects stroke risk via variation in blood pressure

Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.Etude de cohorte sur la santé des étudiantsStopping cognitive decline and dementia by fighting covert cerebral small vessel diseaseStudy on Environmental and GenomeWide predictors of early structural brain Alterations in Young student

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

BACKGROUND: Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. METHODS: For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10(-6)) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10(-8)), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. FINDINGS: We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05-1·12, p=1·48 × 10(-8); minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity-a marker of cerebral small vessel disease-in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2-32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b(-/-) cerebral vessels show decreased smooth muscle cell and pericyte coverage. INTERPRETATION: We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms

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

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease