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1.
Neurology ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32913026

RESUMO

OBJECTIVE: To identify common genetic variants associated with the presence of brain microbleeds (BMB). METHODS: We performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMB were rated on susceptibility-weighted or T2*-weighted gradient echo magnetic resonance imaging sequences, and further classified as lobar, or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMB. RESULTS: BMB were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead SNP rs769449; ORany BMB (95% CI)=1.33 (1.21-1.45); p=2.5x10-10). APOE ε4 alleles were associated with strictly lobar (OR (95% CI)=1.34 (1.19-1.50); p=1.0x10-6) but not with mixed BMB counts (OR (95% CI)=1.04 (0.86-1.25); p=0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral haemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB. CONCLUSIONS: Genetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMB. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

2.
Stroke ; 51(8): 2454-2463, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32693751

RESUMO

BACKGROUND AND PURPOSE: Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. METHODS: The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. RESULTS: In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the HNF1A gene that reached genome-wide significance (P=4.62×10-8) and an additional 29 variants with suggestive evidence of association (P<1×10-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction P value of 2.08×10-3 (0.05/24 unique loci), we were able to validate associations at the HNF1A locus in both SiGN (P=8.18×10-4) and METASTROKE (P=1.72×10-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the HNF1A gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the SFXN4 and TMEM108 genes represent potential novel ischemic stroke loci. CONCLUSIONS: These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.


Assuntos
Afro-Americanos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/genética , Afro-Americanos/etnologia , Estudos de Coortes , Predisposição Genética para Doença/etnologia , Humanos , Acidente Vascular Cerebral/etnologia
3.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 309-330, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32681593

RESUMO

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

4.
Nat Commun ; 11(1): 2175, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32358547

RESUMO

Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perform a transcriptome-wide association study to identify associations with gene expression in relevant tissues, identifying 66 associated genes across the three traits. This genetic study provides insights into the understanding of the biological mechanisms underlying small vessel disease.


Assuntos
Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral/genética , Adulto , Idoso , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Regulação da Expressão Gênica/genética , Ontologia Genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Transcriptoma/genética
5.
Clin Gastroenterol Hepatol ; 18(4): 908-916.e13, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31202982

RESUMO

BACKGROUND & AIMS: Relatives of individuals with Crohn's disease (CD) carry CD-associated genetic variants and are often exposed to environmental factors that increase their risk for this disease. We aimed to estimate the utility of genotype, smoking status, family history, and biomarkers can calculate risk in asymptomatic first-degree relatives of patients with CD. METHODS: We recruited 480 healthy first-degree relatives (full siblings, offspring or parents) of patients with CD through the Guy's and St Thomas' NHS Foundation Trust and from members of Crohn's and Colitis, United Kingdom. DNA samples were genotyped using the Immunochip. We calculated a risk score for 454 participants, based on 72 genetic variants associated with CD, family history, and smoking history. Participants were assigned to highest and lowest risk score quartiles. We assessed pre-symptomatic inflammation by capsule endoscopy and measured 22 markers of inflammation in stool and serum samples (reference standard). Two machine-learning classifiers (elastic net and random forest) were used to assess the ability of the risk factors and biomarkers to identify participants with small intestinal inflammation in the same dataset. RESULTS: The machine-learning classifiers identified participants with pre-symptomatic intestinal inflammation: elastic net (area under the curve, 0.80; 95% CI, 0.62-0.98) and random forest (area under the curve, 0.87; 95% CI, 0.75-1.00). The elastic net method identified 3 variables that can be used to calculate odds for intestinal inflammation: combined family history of CD (odds ratio, 1.31), genetic risk score (odds ratio, 1.14), and fecal calprotectin (odds ratio, 1.04). These same 3 variables were among the 5 factors associated with intestinal inflammation in the random forest model. CONCLUSION: Using machine learning classifiers, we found that genetic variants associated with CD, family history, and fecal calprotectin together identify individuals with pre-symptomatic intestinal inflammation who are therefore at risk for CD. A tool for detecting people at risk for CD before they develop symptoms would help identify the individuals most likely to benefit from early intervention.

6.
Brain ; 143(1): 210-221, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755939

RESUMO

Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.


Assuntos
Coagulação Sanguínea/genética , Fibrinólise/genética , Embolia Intracraniana/sangue , Trombose Intracraniana/sangue , Ativação Plaquetária/genética , Acidente Vascular Cerebral/sangue , Contagem de Células Sanguíneas , Isquemia Encefálica/sangue , Isquemia Encefálica/epidemiologia , Causalidade , Fator VIII/metabolismo , Fator XI/metabolismo , Fibrinogênio/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Embolia Intracraniana/epidemiologia , Trombose Intracraniana/epidemiologia , Análise da Randomização Mendeliana , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia
7.
Hypertension ; 75(2): 365-371, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31865795

RESUMO

We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; ß[SE], 0.38 [0.070]; P=3.8×10-8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; P=5.2×10-6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; ß[SE], 0.47 [0.23]; P=0.047) but not in older adults (ß[SE], -0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Endotélio Vascular/fisiopatologia , Predisposição Genética para Doença , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Vasodilatação/fisiologia , Adolescente , Adulto , Isquemia Encefálica/etiologia , Criança , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Feminino , Seguimentos , Variação Genética , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Cardiovasculares na Gravidez/genética , Complicações Cardiovasculares na Gravidez/metabolismo , Complicações Cardiovasculares na Gravidez/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
8.
J Neurol Sci ; 407: 116526, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31669726

RESUMO

BACKGROUND: Although highly heritable, few genes have been linked to spontaneous intracerebral hemorrhage (SICH), which does not currently have any evidence-based disease-modifying therapy. Individuals of African ancestry are especially susceptible to SICH, even more so for indigenous Africans. We systematically reviewed the genetic variants associated with SICH and examined opportunities for rapidly advancing SICH genomic research for precision medicine. METHOD: We searched the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Genome Wide Association Study (GWAS) catalog and PubMed for original research articles on genetic variants associated with SICH as of 15 June 2019 using the PRISMA guideline. RESULTS: Eight hundred and sixty-four articles were identified using pre-specified search criteria, of which 64 met the study inclusion criteria. Among eligible articles, only 9 utilized GWAS approach while the rest were candidate gene studies. Thirty-eight genetic loci were found to be variously associated with the risk of SICH, hematoma volume, functional outcome and mortality, out of which 8 were from GWAS including APOE, CR1, KCNK17, 1q22, CETP, STYK1, COL4A2 and 17p12. None of the studies included indigenous Africans. CONCLUSION: Given this limited information on the genetic contributors to SICH, more genomic studies are needed to provide additional insights into the pathophysiology of SICH, and develop targeted preventive and therapeutic strategies. This call for additional investigation of the pathogenesis of SICH is likely to yield more discoveries in the unexplored indigenous African populations which also have a greater predilection.


Assuntos
Hemorragia Cerebral/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos
9.
Neurology ; 93(22): e2007-e2020, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31719132

RESUMO

OBJECTIVES: To determine the frequency of rare and pertinent disease-causing variants in small vessel disease (SVD)-associated genes (such as NOTCH3, HTRA1, COL4A1, COL4A2, FOXC1, TREX1, and GLA) in cerebral SVD, we performed targeted gene sequencing in 950 patients with younger-onset apparently sporadic SVD stroke using a targeted sequencing panel. METHODS: We designed a high-throughput sequencing panel to identify variants in 15 genes (7 known SVD genes, 8 SVD-related disorder genes). The panel was used to screen a population of 950 patients with younger-onset (≤70 years) MRI-confirmed SVD stroke, recruited from stroke centers across the United Kingdom. Variants were filtered according to their frequency in control databases, predicted effect, presence in curated variant lists, and combined annotation dependent depletion scores. Whole genome sequencing and genotyping were performed on a subset of patients to provide a direct comparison of techniques. The frequency of known disease-causing and pertinent variants of uncertain significance was calculated. RESULTS: We identified previously reported variants in 14 patients (8 cysteine-changing NOTCH3 variants in 11 patients, 2 HTRA1 variants in 2 patients, and 1 missense COL4A1 variant in 1 patient). In addition, we identified 29 variants of uncertain significance in 32 patients. CONCLUSION: Rare monogenic variants account for about 1.5% of younger onset lacunar stroke. Most are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy variants, but the second most common gene affected is HTRA1. A high-throughput sequencing technology platform is an efficient, reliable method to screen for such mutations.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Acidente Vascular Cerebral Lacunar/genética , Idade de Início , Idoso , CADASIL/genética , Angiopatia Amiloide Cerebral Familiar/genética , Doenças do Tecido Conjuntivo/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Enxaqueca com Aura/genética , Mutação
10.
PLoS One ; 14(10): e0223246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31596875

RESUMO

BACKGROUND: Previous studies of radiological damage in rheumatoid arthritis (RA) have used candidate-gene approaches, or evaluated single genome-wide association studies (GWAS). We undertook the first meta-analysis of GWAS of RA radiological damage to: (1) identify novel genetic loci for this trait; and (2) test previously validated variants. METHODS: Seven GWAS (2,775 RA cases, of a range of ancestries) were combined in a meta-analysis. Radiological damage was assessed using modified Larsen scores, Sharp van Der Heijde scores, and erosive status. Single nucleotide polymophsim (SNP) associations with radiological damage were tested at a single time-point using regression models. Primary analyses included age and disease duration as covariates. Secondary analyses also included rheumatoid factor (RF). Meta-analyses were undertaken in trans-ethnic and European-only cases. RESULTS: In the trans-ethnic primary meta-analysis, one SNP (rs112112734) in close proximity to HLA-DRB1, and strong linkage disequilibrium with the shared-epitope, attained genome-wide significance (P = 4.2x10-8). In the secondary analysis (adjusting for RF) the association was less significant (P = 1.7x10-6). In both trans-ethnic primary and secondary meta-analyses 14 regions contained SNPs with associations reaching P<5x10-6; in the European primary and secondary analyses 13 and 10 regions contained SNPs reaching P<5x10-6, respectively. Of the previously validated SNPs for radiological progression, only rs660895 (tagging HLA-DRB1*04:01) attained significance (P = 1.6x10-5) and had a consistent direction of effect across GWAS. CONCLUSIONS: Our meta-analysis confirms the known association between the HLA-DRB1 shared epitope and RA radiological damage. The lack of replication of previously validated non-HLA markers highlights a requirement for further research to deliver clinically-useful prognostic genetic markers.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Grupos Étnicos/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
11.
Brain ; 142(10): 3176-3189, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430377

RESUMO

Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.


Assuntos
Isquemia Encefálica/genética , Hemorragia Cerebral/genética , Doenças de Pequenos Vasos Cerebrais/genética , Encéfalo , Isquemia Encefálica/complicações , Hemorragia Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/complicações , Feminino , Expressão Gênica/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/genética
12.
Circ Genom Precis Med ; 12(7): e002338, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31306060

RESUMO

BACKGROUND: Genome-wide association studies have identified multiple loci associated with stroke. However, the specific stroke subtypes affected, and whether loci influence both ischemic and hemorrhagic stroke, remains unknown. For loci associated with stroke, we aimed to infer the combination of stroke subtypes likely to be affected, and in doing so assess the extent to which such loci have homogeneous effects across stroke subtypes. METHODS: We performed Bayesian multinomial regression in 16 664 stroke cases and 32 792 controls of European ancestry to determine the most likely combination of stroke subtypes affected for loci with published genome-wide stroke associations, using model selection. Cases were subtyped under 2 commonly used stroke classification systems, TOAST (Trial of Org 10172 Acute Stroke Treatment) and causative classification of stroke. All individuals had genotypes imputed to the Haplotype Reference Consortium 1.1 Panel. RESULTS: Sixteen loci were considered for analysis. Seven loci influenced both hemorrhagic and ischemic stroke, 3 of which influenced ischemic and hemorrhagic subtypes under both TOAST and causative classification of stroke. Under causative classification of stroke, 4 loci influenced both small vessel stroke and intracerebral hemorrhage. An EDNRA locus demonstrated opposing effects on ischemic and hemorrhagic stroke. No loci were predicted to influence all stroke subtypes in the same direction, and only one locus (12q24) was predicted to influence all ischemic stroke subtypes. CONCLUSIONS: Heterogeneity in the influence of stroke-associated loci on stroke subtypes is pervasive, reflecting differing causal pathways. However, overlap exists between hemorrhagic and ischemic stroke, which may reflect shared pathobiology predisposing to small vessel arteriopathy. Stroke is a complex, heterogeneous disorder requiring tailored analytic strategies to decipher genetic mechanisms.


Assuntos
Acidente Vascular Cerebral/genética , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Estudos de Casos e Controles , Europa (Continente) , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
13.
Stroke ; 50(8): 1968-1972, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31221055

RESUMO

Background and Purpose- The role of inflammation in ischemic white matter disease is increasingly recognized, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis (MS) is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesized that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically elevated white matter hyperintensity (WMH) volume was associated with increased MS risk. Methods- We investigated the genetic association in 2 cohorts with magnetic resonance imaging-quantified ischemic white matter lesion volume (WMH in stroke; n=2797 and UK Biobank; n=8353) and 14 802 cases of MS and 26 703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual-level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally, we looked for evidence of overlapping risk across the whole genome. Results- There was no association of genetic variants influencing MS with WMH volume using summary statistics in the WMH in stroke cohort (relative risk score =1.014; 95% CI, 0.936-1.110) or in the UK Biobank cohort (relative risk score =1.030; 95% CI, 0.932-1.117). Conversely, assessing the contribution of single nucleotide polymorphisms significantly associated with WMH on the risk of MS there was no significant association (relative risk score =0.930; 95% CI, 0.736-1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to the selection of single nucleotide polymorphisms at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits. Conclusions- Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischemia and MS. We propose that inflammation acts in distinct pathways because of the differing nature of the primary insult.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Substância Branca/patologia , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
14.
PLoS One ; 14(5): e0214311, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31150407

RESUMO

INTRODUCTION: The UK Biobank (UKB) is a resource that includes detailed health-related data on about 500,000 individuals and is available to the research community. However, several obstacles limit immediate analysis of the data: data files vary in format, may be very large, and have numerical codes for column names. RESULTS: ukbtools removes all the upfront data wrangling required to get a single dataset for statistical analysis. All associated data files are merged into a single dataset with descriptive column names. The package also provides tools to assist in quality control by exploring the primary demographics of subsets of participants; query of disease diagnoses for one or more individuals, and estimating disease frequency relative to a reference variable; and to retrieve genetic metadata. CONCLUSION: Having a dataset with meaningful variable names, a set of UKB-specific exploratory data analysis tools, disease query functions, and a set of helper functions to explore and write genetic metadata to file, will rapidly enable UKB users to undertake their research.


Assuntos
Sistemas de Gerenciamento de Base de Dados , Conjuntos de Dados como Assunto , Registros Eletrônicos de Saúde , Armazenamento e Recuperação da Informação , Análise de Dados , Doença , Humanos , Metadados , Reino Unido
16.
Neurology ; 92(12): e1271-e1283, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30796134

RESUMO

OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8. RESULTS: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). CONCLUSIONS: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.


Assuntos
Isquemia Encefálica/genética , Acidente Vascular Cerebral/genética , Isquemia Encefálica/terapia , Estudo de Associação Genômica Ampla , Humanos , Recuperação de Função Fisiológica/genética , Acidente Vascular Cerebral/terapia
17.
Neurology ; 92(9): e944-e950, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30804065

RESUMO

OBJECTIVE: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. METHODS: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). RESULTS: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. CONCLUSIONS: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.


Assuntos
Isquemia Encefálica/genética , Cálcio/sangue , Embolia Intracraniana/genética , Magnésio/sangue , Acidente Vascular Cerebral/genética , Isquemia Encefálica/sangue , Humanos , Embolia Intracraniana/sangue , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/sangue
18.
Ann Neurol ; 85(4): 495-501, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30785218

RESUMO

OBJECTIVE: Trials of B vitamin therapy to lower blood total homocysteine (tHcy) levels for prevention of stroke are inconclusive. Secondary analyses of trial data and epidemiological studies suggest that tHcy levels may be particularly associated with small vessel stroke (SVS). We assessed whether circulating tHcy and B vitamin levels are selectively associated with SVS, but not other stroke subtypes, using Mendelian randomization. METHODS: We used summary statistics data for single-nucleotide polymorphisms (SNPs) associated with tHcy (n = 18), folate (n = 3), vitamin B6 (n = 1), and vitamin B12 (n = 14) levels, and the corresponding data for stroke from the MEGASTROKE consortium (n = 16,952 subtyped ischemic stroke cases and 404,630 noncases). RESULTS: Genetically predicted tHcy was associated with SVS, with an odds ratio of 1.34 (95% confidence interval [CI], 1.13-1.58; p = 6.7 × 10-4 ) per 1 standard deviation (SD) increase in genetically predicted tHcy levels, but was not associated with large artery or cardioembolic stroke. The association was mainly driven by SNPs at or near the MTHFR and MUT genes. The odds ratios of SVS per 1 SD increase in genetically predicted folate and vitamin B6 levels were 0.49 (95% CI, 0.34-0.71; p = 1.3 × 10-4 ) and 0.70 (95% CI, 0.52-0.94; p = 0.02), respectively. Genetically higher vitamin B12 levels were not associated with any stroke subtype. INTERPRETATION: These findings suggest that any effect of homocysteine-lowering treatment in preventing stroke will be confined to the SVS subtype. Whether genetic variants at or near the MTHFR and MUT genes influence SVS risk through pathways other than homocysteine levels and downstream effects require further investigation. Ann Neurol 2019;85:495-501.


Assuntos
Isquemia Encefálica/genética , Homocisteína/genética , Análise da Randomização Mendeliana/métodos , Acidente Vascular Cerebral/genética , Isquemia Encefálica/sangue , Isquemia Encefálica/prevenção & controle , Homocisteína/antagonistas & inibidores , Homocisteína/sangue , Humanos , Microvasos/patologia , Polimorfismo de Nucleotídeo Único/genética , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/prevenção & controle , Vitamina B 12/uso terapêutico
19.
Stroke ; 50(2): 283-290, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30636574

RESUMO

Background and Purpose- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke usually presenting with migraine with aura, lacunar infarcts, and cognitive impairment. Acute encephalopathy is a less recognized presentation of the disease. Methods- Data collected prospectively from 340 consecutively recruited symptomatic patients with diagnosis of CADASIL seen in a British National CADASIL clinic was retrospectively reviewed and original clinical records and imaging obtained. An encephalopathic event was defined as an acute event of an altered state of consciousness in a patient with CADASIL, manifesting with signs of brain dysfunction, which warranted hospital admission in the absence of any other cause. Clinical characteristics, risk factors, and outcome of encephalopathic presentations were studied. Results- A total of 35 of 340 (10.3%) participants had a history of 50 encephalopathic events which was the first hospital presentation of CADASIL in 33 (94.3%) patients. Most commonly reported features during episodes were visual hallucinations (44%), seizures (22%), and focal neurological deficits (60%).Complete recovery within 3 months was reported in 48(96%) episodes. In 62% of episodes, there was a history of migraine or migraine aura directly preceding the encephalopathy. In 2 out of 15 cases where magnetic resonance imaging during episodes was available, unilateral focal cortical swelling was seen. A past history of migraine was independently associated with encephalopathy (odds ratio=12.3 [95% CI, 1.6-93.7]; P=0.015). Conclusions- In up to 10% of CADASIL patients, a reversible encephalopathy is the first presentation leading to diagnosis. The strong association with migraine suggests a shared pathogenesis. Focal cortical swelling may be seen on magnetic resonance imaging during the acute episode.


Assuntos
Encéfalo/patologia , CADASIL/patologia , Adulto , Encéfalo/diagnóstico por imagem , Edema Encefálico/etiologia , CADASIL/diagnóstico por imagem , CADASIL/genética , Depressão Alastrante da Atividade Elétrica Cortical , Diagnóstico Tardio , Eletroencefalografia , Feminino , Alucinações/etiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/etiologia , Mutação de Sentido Incorreto , Neuroimagem , Receptor Notch3/genética , Estudos Retrospectivos , Fatores de Risco , Convulsões/etiologia , Adulto Jovem
20.
Neurology ; 92(8): e749-e757, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30659137

RESUMO

OBJECTIVE: To identify novel genetic associations with white matter hyperintensities (WMH). METHODS: We performed a genome-wide association meta-analysis of WMH volumes in 11,226 individuals, including 8,429 population-based individuals from UK Biobank and 2,797 stroke patients. Replication of novel loci was performed in an independent dataset of 1,202 individuals. In all studies, WMH were quantified using validated automated or semi-automated methods. Imputation was to either the Haplotype Reference Consortium or 1,000 Genomes Phase 3 panels. RESULTS: We identified a locus at genome-wide significance in an intron of PLEKHG1 (rs275350, ß [SE] = 0.071 [0.013]; p = 1.6 × 10-8), a Rho guanine nucleotide exchange factor that is involved in reorientation of cells in the vascular endothelium. This association was validated in an independent sample (overall p value, 2.4 × 10-9). The same single nucleotide polymorphism was associated with all ischemic stroke (odds ratio [OR] [95% confidence interval (CI)] 1.07 [1.03-1.12], p = 0.00051), most strongly with the small vessel subtype (OR [95% CI] 1.09 [1.00-1.19], p = 0.044). Previous associations at 17q25 and 2p16 reached genome-wide significance in this analysis (rs3744020; ß [SE] = 0.106 [0.016]; p = 1.2 × 10-11 and rs7596872; ß [SE] = 0.143 [0.021]; p = 3.4 × 10-12). All identified associations with WMH to date explained 1.16% of the trait variance in UK Biobank, equivalent to 6.4% of the narrow-sense heritability. CONCLUSIONS: Genetic variation in PLEKHG1 is associated with WMH and ischemic stroke, most strongly with the small vessel subtype, suggesting it acts by promoting small vessel arteriopathy.


Assuntos
Isquemia Encefálica/genética , Doenças de Pequenos Vasos Cerebrais/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Acidente Vascular Cerebral/genética , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Isquemia Encefálica/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/diagnóstico por imagem , Acidente Vascular Cerebral Lacunar/genética
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