A genome-wide association study links small-vessel ischemic stroke to autophagy.
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ABSTRACT:
SUBMITTER: Lee TH
PROVIDER: S-EPMC5680343 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
A genome-wide association study links small-vessel ischemic stroke to autophagy.
Lee Tsong-Hai TH Ko Tai-Ming TM Chen Chien-Hsiun CH Chang Yeu-Jhy YJ Lu Liang-Suei LS Chang Chien-Hung CH Huang Kuo-Lun KL Chang Ting-Yu TY Lee Jiann-Der JD Chang Ku-Chou KC Yang Jen-Tsung JT Wen Ming-Shien MS Wang Chao-Yung CY Chen Ying-Ting YT Chen Tsai-Chuan TC Chou Shu-Yu SY Lee Ming-Ta Michael MM Chen Yuan-Tsong YT Wu Jer-Yuarn JY
Scientific reports 20171109 1
Genome-wide association studies (GWAS) can serve as strong evidence in correlating biological pathways with human diseases. Although ischemic stroke has been found to be associated with many biological pathways, the genetic mechanism of ischemic stroke is still unclear. Here, we performed GWAS for a major subtype of stroke-small-vessel occlusion (SVO)-to identify potential genetic factors contributing to ischemic stroke. GWAS were conducted on 342 individuals with SVO stroke and 1,731 controls f ...[more]
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Project description:Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 × 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
| S-EPMC3303115 | biostudies-literature
Project description:BackgroundIschemic stroke is a major cause of death and disability in the world. A major ischemic stroke subtype, large-vessel ischemic stroke (large artery atherosclerosis; LAA), has been shown to have some genetic components in individuals of European ancestry. However, it is not clear whether the genetic predisposition to LAA stroke varies among ethnicities. We sought to identify genetic factors that contribute to LAA stroke in 2 independent samples of Han Chinese individuals.Methods and resultsNovel genetic variants that predispose individuals to LAA stroke were identified using a genome-wide association study (GWAS) of 444 individuals with LAA stroke and 1727 controls in a Han Chinese population residing in Taiwan. The study was replicated in an independent Han Chinese population comprising an additional 319 cases and 1802 controls. We identified 5 single-nucleotide polymorphisms, including rs2415317 (P=3.10×10(-8)), rs934075 (P=4.00×10(-9)), rs944289 (P=3.57×10(-8)), rs2787417 (P=1.76×10(-8)), and rs1952706 (P=2.92×10(-8)), at one novel locus on chromosome 14q13.3 within PTCSC3 (encoding papillary thyroid carcinoma susceptibility candidate 3) that were associated with LAA stroke at genome-wide significance (P<5×10(-8)).ConclusionsOur data provide strong support for future studies on the role of PTCSC3 in the pathogenesis of LAA stroke and the association between LAA stroke development and thyroid function. In addition, these findings provide insights into the genetic basis of LAA stroke and identify a novel pathway that might be applicable for future therapeutic intervention.
| S-EPMC4943273 | biostudies-literature
Project description: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.
| S-EPMC6763741 | biostudies-literature
Project description:Background and purposeCerebral small vessel disease (SVDs) are related with large artery atherosclerosis. However, the association between aortic atheroma (AA) and cerebral small vessel disease has rarely been reported. This study evaluated the relationship between presence and burden of AAs and those of SVDs in patients with acute ischemic stroke.MethodsWe included 737 consecutive patients who underwent transesophageal echocardiography (TEE) and brain magnetic resonance imaging (MRI) for evaluation of acute stroke. AA subtypes were classified as complex aortic plaque (CAP) and simple aortic plaque (SAP). Presence and burden of SVDs including cerebral microbleeds (CMBs), white matter hyperintensities (WMHs), perivascular spaces (PVSs), asymptomatic lacunar infarctions (ALIs), and total SVD score, were investigated.ResultsAA was found by TEE in 360 (48.8%) patients including 11.6% with CAP and 37.2% with SAP. One or more types of SVDs was found in 269 (36.4%) patients. In multivariable analysis, presence of CMBs (odds ratio [OR] 4.68), high-grade WMHs (OR 3.13), high-grade PVSs (OR 3.35), and ALIs (OR 4.24) were frequent in patients with AA than those without AA. Each 1-point increase in total SVD score increased the odds of presence of CAP (OR 1.94, 95% confidence interval (CI) 1.44-1.85) and SAP (OR 1.54, 95% CI 1.35-1.75).ConclusionsIn this study, patients with AA frequently had cerebral SVDs. Larger burden of AA was associated with advanced cerebral SVDs. Our findings give an additional information for positive relationship with systemic atherosclerosis and coexisting cerebral SVDs in acute ischemic stroke patients.
| S-EPMC5066433 | biostudies-literature
Project description:Ischemic stroke (IS) is among the leading causes of death in Western countries. There is a significant genetic component to IS susceptibility, especially among young adults. To date, research to identify genetic loci predisposing to stroke has met only with limited success. We performed a genome-wide association (GWA) analysis of early-onset IS to identify potential stroke susceptibility loci. The GWA analysis was conducted by genotyping 1 million SNPs in a biracial population of 889 IS cases and 927 controls, ages 15-49 years. Genotypes were imputed using the HapMap3 reference panel to provide 1.4 million SNPs for analysis. Logistic regression models adjusting for age, recruitment stages, and population structure were used to determine the association of IS with individual SNPs. Although no single SNP reached genome-wide significance (P < 5 × 10(-8)), we identified two SNPs in chromosome 2q23.3, rs2304556 (in FMNL2; P = 1.2 × 10(-7)) and rs1986743 (in ARL6IP6; P = 2.7 × 10(-7)), strongly associated with early-onset stroke. These data suggest that a novel locus on human chromosome 2q23.3 may be associated with IS susceptibility among young adults.
| S-EPMC3276159 | biostudies-literature
Project description:BACKGROUND AND PURPOSE:Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. METHODS:The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. CONCLUSIONS:The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.
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Project description:Background and Purpose- Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke. Methods- Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed. Results- Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance (P<5×10-8). The 14q24.3 locus was associated with acute stroke outcome (rs112809786, P=0.036) and with ACOT1 and PTGR2 gene expression. Previous polymorphisms associated with leukocyte counts in general-population did not show any significance in our study. Conclusions- We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions.
| S-EPMC6878188 | biostudies-literature
Project description: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.
| S-EPMC7195435 | biostudies-literature
Project description:BackgroundGenetic 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.MethodsFor 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.FindingsWe 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.InterpretationWe 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.FundingNIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.
| S-EPMC4943223 | biostudies-literature
Project description:ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe 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.ResultsWe 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).ConclusionsIn 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.
| S-EPMC6511098 | biostudies-literature