The migraine–stroke connection: A genetic perspective

Background A complex relationship between migraine and vascular disease has long been recognized. The pathophysiological basis underlying this correlation is incompletely understood. Aim The aim of this review is to focus on the migraine–vascular disorders connection from a genetic perspective, illustrating potentially shared (molecular) mechanisms. Results We first summarize the clinical presentation and genetic basis of CADASIL and other monogenic vascular syndromes with migraine as a prominent disease manifestation. Based on data from transgenic mouse models for familial hemiplegic migraine, we then discuss cortical spreading depression as a potential mechanistic link between migraine and ischemic stroke. Finally, we review data from genome-wide association studies, with a focus on overlapping findings with cervical artery dissection, ischemic stroke in general and cardiovascular disease. Conclusion A wealth of data supports a genetic link between migraine and vascular disease. Based on growing high-throughput data-sets, new genotyping techniques and in-depth phenotyping, further insights are expected for the future.

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TTC7B Emerges as a Novel Risk Factor for Ischemic Stroke Through the Convergence of Several Genome-Wide Approaches

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.24 ◽

2012 ◽

Vol 32 (6) ◽

pp. 1061-1072 ◽

Cited By ~ 39

Author(s):

Tiago Krug ◽

João Paulo Gabriel ◽

Ricardo Taipa ◽

Benedita V Fonseca ◽

Sophie Domingues-Montanari ◽

...

Keyword(s):

Ischemic Stroke ◽

Mononuclear Cells ◽

Association Studies ◽

Differentially Expressed ◽

Data Sets ◽

Genome Wide Association Studies ◽

Peripheral Blood Mononuclear ◽

Pathogenic Potential ◽

Novel Approach ◽

Genome Wide

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5–intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

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Using Human Genetics to Understand Mechanisms in Ischemic Stroke Outcome: From Early Brain Injury to Long-Term Recovery

Stroke ◽

10.1161/strokeaha.121.032622 ◽

2021 ◽

Author(s):

Jin-Moo Lee ◽

Israel Fernandez-Cadenas ◽

Arne G. Lindgren

Keyword(s):

Ischemic Stroke ◽

Brain Injury ◽

Drug Targets ◽

Molecular Mechanisms ◽

Association Studies ◽

Early Brain Injury ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Stroke Outcome ◽

Genome Wide

There is a critical need to elucidate molecular mechanisms underlying brain injury, repair, and recovery following ischemic stroke—a global health problem with major social and economic impact. Despite 5 decades of intensive research, there are no widely accepted neuroprotective drugs that mitigate ischemic brain injury, or neuroreparative drugs, or personalized approaches that guide therapies to enhance recovery. We here explore novel reverse translational approaches that will complement traditional forward translational methods in identifying mechanisms relevant to human stroke outcome. Although genome-wide association studies have yielded over 30 genetic loci that influence ischemic stroke risk, only a few genome-wide association studies have been performed for stroke outcome. We discuss important considerations for genetic studies of ischemic stroke outcome—including carefully designed phenotypes that capture injury/recovery mechanisms, anchored in time to stroke onset. We also address recent genome-wide association studies that provide insight into mechanisms underlying brain injury and repair. There are several ongoing initiatives exploring genomic associations with novel phenotypes related to stroke outcome. To improve the understanding of the genetic architecture of ischemic stroke outcome, larger studies using standardized phenotypes, preferably embedded in standard-of-care measures, are needed. Novel techniques beyond genome-wide association studies—including exploiting informatics, multi-omics, and novel analytics—promise to uncover genetic and molecular pathways from which drug targets and other new interventions may be identified.

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PHACTR1 genetic variability is not critical in small vessel ischemic disease patients and PcomA recruitment in C57BL/6J mice

Scientific Reports ◽

10.1038/s41598-021-84919-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Clemens Messerschmidt ◽

Marco Foddis ◽

Sonja Blumenau ◽

Susanne Müller ◽

Kajetan Bentele ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Variability ◽

Critical Role ◽

Small Vessel ◽

Artery Dissection ◽

Cervical Artery Dissection ◽

Genome Wide Association Studies ◽

Ischemic Disease ◽

Collateral Arteries ◽

Coding Variants

AbstractRecently, several genome-wide association studies identified PHACTR1 as key locus for five diverse vascular disorders: coronary artery disease, migraine, fibromuscular dysplasia, cervical artery dissection and hypertension. Although these represent significant risk factors or comorbidities for ischemic stroke, PHACTR1 role in brain small vessel ischemic disease and ischemic stroke most important survival mechanism, such as the recruitment of brain collateral arteries like posterior communicating arteries (PcomAs), remains unknown. Therefore, we applied exome and genome sequencing in a multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic brain small vessel ischemic disease and CADASIL-like Caucasian patients from US, Portugal, Finland, Serbia and Turkey and in 2 C57BL/6J stroke mouse models (bilateral common carotid artery stenosis [BCCAS] and middle cerebral artery occlusion [MCAO]), characterized by different degrees of PcomAs patency. We report 3 very rare coding variants in the small vessel ischemic disease-CADASIL-like cohort (p.Glu198Gln, p.Arg204Gly, p.Val251Leu) and a stop-gain mutation (p.Gln273*) in one MCAO mouse. These coding variants do not cluster in PHACTR1 known pathogenic domains and are not likely to play a critical role in small vessel ischemic disease or brain collateral circulation. We also exclude the possibility that copy number variants (CNVs) or a variant enrichment in Phactr1 may be associated with PcomA recruitment in BCCAS mice or linked to diverse vascular traits (cerebral blood flow pre-surgery, PcomA size, leptomeningeal microcollateral length and junction density during brain hypoperfusion) in C57BL/6J mice, respectively. Genetic variability in PHACTR1 is not likely to be a common susceptibility factor influencing small vessel ischemic disease in patients and PcomA recruitment in C57BL/6J mice. Nonetheless, rare variants in PHACTR1 RPEL domains may influence the stroke outcome and are worth investigating in a larger cohort of small vessel ischemic disease patients, different ischemic stroke subtypes and with functional studies.

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Molecular Mechanisms of ZC3H12C/Reg-3 Biological Activity and Its Involvement in Psoriasis Pathology

International Journal of Molecular Sciences ◽

10.3390/ijms22147311 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7311

Author(s):

Mateusz Wawro ◽

Jakub Kochan ◽

Weronika Sowinska ◽

Aleksandra Solecka ◽

Karolina Wawro ◽

...

Keyword(s):

Family Member ◽

Cellular Localization ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Association Studies ◽

Psoriasis Patient ◽

Genome Wide Association Studies ◽

Mrna Levels ◽

Transcript Levels

The members of the ZC3H12/MCPIP/Regnase family of RNases have emerged as important regulators of inflammation. In contrast to Regnase-1, -2 and -4, a thorough characterization of Regnase-3 (Reg-3) has not yet been explored. Here we demonstrate that Reg-3 differs from other family members in terms of NYN/PIN domain features, cellular localization pattern and substrate specificity. Together with Reg-1, the most comprehensively characterized family member, Reg-3 shared IL-6, IER-3 and Reg-1 mRNAs, but not IL-1β mRNA, as substrates. In addition, Reg-3 was found to be the only family member which regulates transcript levels of TNF, a cytokine implicated in chronic inflammatory diseases including psoriasis. Previous meta-analysis of genome-wide association studies revealed Reg-3 to be among new psoriasis susceptibility loci. Here we demonstrate that Reg-3 transcript levels are increased in psoriasis patient skin tissue and in an experimental model of psoriasis, supporting the immunomodulatory role of Reg-3 in psoriasis, possibly through degradation of mRNA for TNF and other factors such as Reg-1. On the other hand, Reg-1 was found to destabilize Reg-3 transcripts, suggesting reciprocal regulation between Reg-3 and Reg-1 in the skin. We found that either Reg-1 or Reg-3 were expressed in human keratinocytes in vitro. However, in contrast to robustly upregulated Reg-1 mRNA levels, Reg-3 expression was not affected in the epidermis of psoriasis patients. Taken together, these data suggest that epidermal levels of Reg-3 are negatively regulated by Reg-1 in psoriasis, and that Reg-1 and Reg-3 are both involved in psoriasis pathophysiology through controlling, at least in part different transcripts.

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Polygenic Risk Score of Longevity Predicts Longer Survival Across an Age Continuum

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa289 ◽

2020 ◽

Author(s):

Niccolo’ Tesi ◽

Sven J van der Lee ◽

Marc Hulsman ◽

Iris E Jansen ◽

Najada Stringa ◽

...

Keyword(s):

Older Adults ◽

Cellular Response ◽

Molecular Mechanisms ◽

Association Studies ◽

Risk Scores ◽

Human Longevity ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Age Related

Abstract Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic risk scores (PRSs) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N = 343), a population-matched cohort of older adults from 5 cohorts (N = 2905), and summary statistics data from genome-wide association studies on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older adults. This PRS was also associated with longer survival in an independent sample of younger individuals (p = .02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the APOE-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human life span is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

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Magnetic Resonance Imaging and Clinical Factors Associated With Ischemic Stroke in Patients Suspected of Cervical Artery Dissection

Stroke ◽

10.1161/strokeaha.118.021868 ◽

2018 ◽

Vol 49 (10) ◽

pp. 2337-2344 ◽

Cited By ~ 5

Author(s):

J. Scott McNally ◽

Peter J. Hinckley ◽

Akihiko Sakata ◽

Laura B. Eisenmenger ◽

Seong-Eun Kim ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Ischemic Stroke ◽

Magnetic Resonance ◽

Artery Dissection ◽

Cervical Artery Dissection ◽

Resonance Imaging ◽

Clinical Factors ◽

Factors Associated ◽

Cervical Artery

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Involvement of astrocyte and oligodendrocyte gene sets in migraine

Cephalalgia ◽

10.1177/0333102415618614 ◽

2015 ◽

Vol 36 (7) ◽

pp. 640-647 ◽

Cited By ~ 8

Author(s):

Else Eising ◽

Christiaan de Leeuw ◽

Josine L Min ◽

Verneri Anttila ◽

Mark HG Verheijen ◽

...

Keyword(s):

Migraine With Aura ◽

Genetic Background ◽

Migraine Without Aura ◽

Protein Modification ◽

Association Studies ◽

Cell Types ◽

Familial Hemiplegic Migraine ◽

Genome Wide Association Studies ◽

Brain Disorder ◽

Gene Sets

Background Migraine is a common episodic brain disorder characterized by recurrent attacks of severe unilateral headache and additional neurological symptoms. Two main migraine types can be distinguished based on the presence of aura symptoms that can accompany the headache: migraine with aura and migraine without aura. Multiple genetic and environmental factors confer disease susceptibility. Recent genome-wide association studies (GWAS) indicate that migraine susceptibility genes are involved in various pathways, including neurotransmission, which have already been implicated in genetic studies of monogenic familial hemiplegic migraine, a subtype of migraine with aura. Methods To further explore the genetic background of migraine, we performed a gene set analysis of migraine GWAS data of 4954 clinic-based patients with migraine, as well as 13,390 controls. Curated sets of synaptic genes and sets of genes predominantly expressed in three glial cell types (astrocytes, microglia and oligodendrocytes) were investigated. Discussion Our results show that gene sets containing astrocyte- and oligodendrocyte-related genes are associated with migraine, which is especially true for gene sets involved in protein modification and signal transduction. Observed differences between migraine with aura and migraine without aura indicate that both migraine types, at least in part, seem to have a different genetic background.

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Enriching human interactome with functional mutations to detect high-impact network modules underlying complex diseases

10.1101/786798 ◽

2019 ◽

Author(s):

Hongzhu Cui ◽

Suhas Srinivasan ◽

Dmitry Korkin

Keyword(s):

Biological Networks ◽

Molecular Mechanisms ◽

Association Studies ◽

Genetic Diseases ◽

Detection Methods ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Human Interactome ◽

Module Detection ◽

Disease Module

AbstractProgress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, DIMSUM, which enables the integration of genome-wide association studies (GWAS), functional effects of mutations, and protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for disease module analysis, facilitating discovery of new disease markers.

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