International Stroke Genetics Consortium Research Articles

Identification of immune-inflammation targets for intracranial aneurysms: A multiomics and epigenome-wide study integrating summary-data-based mendelian randomization, single-cell-type expression analysis, and DNA methylation regulation.

Dysfunction of the immune system and inflammation plays a vital role in developing intracranial aneurysms (IAs). However, the progress of genetic pathophysiology is complicated and not entirely elaborated. This study aimed to explore the genetic associations of immune- and inflammation-related genes (IIRGs) with IAs and their subtypes using Mendelian randomization, colocalization test, and integrated multiomics functional analysis. We conducted a summary-data-based Mendelian randomization (SMR) analysis using data from several genome-wide association studies of gene expression (31,684 European individuals) and protein quantitative trait loci (35,559 Icelanders), as well as information on IAs and their subtypes from The International Stroke Genetics Consortium (IGSC) for discovery phase and the FinnGen study for replication. This analysis aimed to determine the causal relationship between IIRGs and the risk of IAs and their subtypes. Further functional analyses, including DNA methylation regulation (1980, European individuals), single-cell-type expression analysis, and protein-protein interaction, were conducted to detect the specific cell type with enriched expression and discover potential drug targets. After integrating multi-omics evidence from expression quantitative trait loci (eQTL)and protein quantitative trait loci(pQTL), we found that tier 1: RELT [odds ratio (OR): 0.14, 95% confidence interval (CI): 0.04-0.50], TNFSF12 (OR: 1.24, 95% CI: 1.24-1.43), tier 3:ICAM5 (OR: 0.89, 95% CI: 0.82-0.96), and ERAP2 (OR: 1.07, 95% CI: 1.02-1.12) were associated with the risk of IAs; tier 3: RELT (OR: 0.11, 95% CI: 0.02-0.54), ERAP2 (OR: 1.08, 95% CI: 1.02-1.13), and TNFSF12 (OR: 1.24, 95% CI: 1.05-1.47) were associated with the risk of aneurysmal subarachnoid hemorrhage (aSAH); and tier 1:RELT (OR: 0.04, 95% CI: 0.01-0.30) was associated with the risk of unruptured intracranial aneurysms (uIAs). Further functional analyses showed that RELT was regulated by cg06382664 and cg18850434 and ICAM5 was regulated by cg04295144 in IAs; RELT was regulated by cg06382664, cg08770935, cg16533363, and cg18850434 in aSAH; and RELT was regulated by cg06382664 and cg21810604 in uIAs. In addition, we found that H6PD (OR: 1.13, 95% CI: 1.01-1.28), NT5M (OR: 1.91, 95% CI: 1.21-3.01), and NPTXR (OR: 1.13, 95% CI: 1.01-1.26) were associated with IAs; NT5M (OR: 2.13, 95% CI: 1.23-3.66) was associated aSAH; and AP4M1 (OR: 0.06, 95% CI: 0.01-0.42) and STX7 (OR: 3.97, 95% CI: 1.41-11.18) were related to uIAs. STX7 and TNFSF12 were mainly enriched in microglial cells, whereas H6PD, STX7, and TNFSF12 were mainly enriched in astrocytes. After integrating multi-omics evidence, we eventually identified IIRGs: RELT, TNFSF12, ICAM5 and ERAP2 were the novel therapy targets for IAs. These new results confirmed a vital role of immune and inflammation in the etiology of IAs, contributing to enhance our understanding of the immune and inflammatory mechanisms in the pathogenesis of IAs and revealing the complex genetic causality of IAs.

Exploring Stroke Risk through Mendelian Randomization: A Comprehensive Study Integrating Genetics and Metabolic Traits in the Korean Population.

Numerous risk factors play a role in the causation of stroke, and the cardiometabolic condition is a one of the most important. In Korea, various treatment methods are employed based on the constitutional type, which is known to differ significantly in cardiometabolic disease. In this study, we compared the estimates obtained for different groups by applying the Mendelian randomization method to investigate the causal effects of genetic characteristics on stroke, according to constitutional type. In clinical analysis, the subtypes differ significantly in diabetes or dyslipidemia. The genetic association estimates for the stroke subtype risk were obtained from MEGASTROKE, the International Stroke Genetics Consortium (ISGC), UKbiobank, and BioBank Japan (BBJ), using group-related SNPs as instrumental variables. The TE subtypes with higher risk of metabolic disease were associated with increased risk (beta = 4.190; s.e. = 1.807; p = 0.035) of cardioembolic stroke (CES), and the SE subtypes were associated with decreased risk (beta = -9.336, s.e. = 1.753; p = 3.87 × 10-5) of CES. The findings highlight the importance of personalized medicine in assessing disease risk based on an individual's constitutional type.

Causal association between circulating inflammatory cytokines and intracranial aneurysm and subarachnoid hemorrhage.

The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. The summary-level datasets for inflammatory cytokines were extracted from a genome-wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome-wide association study meta-analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein-1 Alpha (MIP_1A), MIP_1A and interferon γ-induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta-analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms.

Causal relationship between telomere length and risk of intracranial aneurysm: a bidirectional Mendelian randomization study.

Telomere length is closely linked to the aging phenotype, where cellular aging results in the production of a cascade of cell factors and the senescence-associated secretory phenotype (SASP), leading to an inflammatory response. The presence of inflammation plays a crucial role in the formation of intracranial aneurysms. Nevertheless, the relationship between telomere length and intracranial aneurysms remains unclear. This study aims to explore the causal connection between telomere length and intracranial aneurysms through the utilization of Mendelian randomization (MR) analysis. Data on telomere length were obtained from the genome-wide association studies conducted on the UK Biobank, comprising a total of 472,174 participants. Data on intracranial aneurysms were obtained from the summary dataset of the Global Genome-wide Association Study (GWAS) conducted by the International Stroke Genetics Consortium. The dataset consisted of 7,495 cases and 71,934 controls, all of European descent. Initially, the linkage disequilibrium score was used to investigate the connection between telomere length and intracranial aneurysms. Subsequently, a bidirectional MR was conducted using two-sample analysis to assess whether there is a causal connection between telomere length and intracranial aneurysm risk. The results were analyzed utilizing five MR methods, with the inverse variance weighted method serving as the main methodology. In addition, we did various analyses to evaluate the presence of heterogeneity, pleiotropy, and sensitivity in the study results. A reverse MR analysis was conducted to investigate potential reverse causal links. In the forward MR analysis, it was observed that both the inverse variance-weighted and weighted median analyses implied a potential causal relationship between longer telomere length and a decreased incidence of intracranial aneurysms (IVW: OR = 0.66, 95% CI: 0.47-0.92, p = 1.49 × 10-2). There was no heterogeneity or horizontal pleiotropy. The findings were verified to be robust through the utilization of leave-one-out analysis. The use of reverse MR analysis did not establish a potential causal link between the occurrence of intracranial aneurysms and telomere length. There may exist a potential correlation between longer telomere length and a decreased likelihood of intracranial aneurysms within the European population. The present study offers novel insights into the correlation between telomere length and intracranial aneurysms. Additional research is required to clarify the underlying mechanisms and validate our discoveries in diverse populations.

Mendelian randomization of stroke risk after total hip and knee replacements.

Previous epidemiological studies have indicated an increased risk of neurovascular diseases in patients following total hip and knee replacements. However, definitive conclusions regarding the increased risk of stroke post-replacement remain elusive. Therefore, we conducted a two-sample Mendelian randomization study to investigate the causal relationship between total hip and knee replacements and stroke. We utilized summary data from publicly available genome-wide association studies (GWAS). Data concerning total hip replacements (THR, N = 319,037) and total knee replacements (TKR, N = 252,041) were sourced from the Genetics of Osteoarthritis (GO) Consortium. Stroke-related data were obtained from the International Stroke Genetics Consortium, encompassing any stroke (AS), any ischemic stroke (AIS), large vessel ischemic stroke (LV-IS), cardioembolic ischemic stroke (CE-IS), and small vessel ischemic stroke (SV-IS). Our primary causal inference method was the inverse variance weighted (IVW) approach, supplemented by weighted median and MR-Egger regression as secondary inference methods. We utilized the MR-PRESSO global test for outlier detection, Cochran's Q statistic to assess heterogeneity, and assessed the multiplicity and stability of our findings using p-values from MR-PRESSO and MR-Egger regressions, and the leave-one-out method, respectively. We identified significant genetic associations between THR and both AS (IVW p = 0.0001, OR = 1.08, 95% CI = 1.04-1.12) and AIS (IVW p = 0.0016, OR = 1.07, 95% CI = 1.03-1.12). Significant associations were also observed between TKR and AS (IVW p = 0.0002, OR = 1.08, 95% CI = 1.04-1.12), as well as AIS (IVW p = 0.0005, OR = 1.15, 95% CI = 1.06-1.24). Our findings genetically support an increased risk of stroke following total hip and knee replacements. However, further studies are necessary to elucidate the specific mechanisms underlying stroke episodes post-replacement.

Causal relationships between human blood metabolites and intracranial aneurysm and aneurysmal subarachnoid hemorrhage: a Mendelian randomization study.

The aim of this study was to assess the causal relationships between blood metabolites and intracranial aneurysm, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysm. Our exposure sample consisted of 7,824 individuals from a genome-wide association study of human blood metabolites. Our outcome sample consisted of 79,429 individuals (7,495 cases and 71,934 controls) from the International Stroke Genetics Consortium, which conducted a genome-wide association study of intracranial aneurysm, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysm. We identified blood metabolites with a potential causal effect on intracranial aneurysms and conducted sensitivity analyses to validate our findings. After rigorous screening and Mendelian randomization tests, we found four, two, and three serum metabolites causally associated with intracranial aneurysm, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysm, respectively (all P < 0.05). Sensitivity analyses confirmed the robustness of these associations. Our Mendelian randomization analysis demonstrated causal relationships between human blood metabolites and intracranial aneurysm, aneurysmal subarachnoid hemorrhage, and unruptured intracranial aneurysm. Further research is required to explore the potential of targeting these metabolites in the management of intracranial aneurysm.

Inflammatory bowel disease and the risk of intracerebral hemorrhage: A Mendelian randomization study and meta-analysis.

The link between inflammatory bowel disease (IBD) and intracerebral hemorrhage (ICH) is still unclear. We conducted a Mendelian randomization research and meta-analysis to explore the impact of IBD and its subtypes (Crohn's disease [CD], ulcerative colitis [UC]) on the risk of ICH. Two large genome-wide association analysis studies of International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and International Stroke Genetics Consortium as exposure (IBD, UC, and CD) and outcome (ICH) in the initial stage. IBD, CD, UC GWAS data from the FinnGen consortium were adopted for the replication phase, and ultimately, the results of the initial stage and replication phase data were combined in a meta-analysis to evaluate the causal association between IBD and its subtypes and the risk of ICH. In the initial stage, we found that in the IVW (odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.71-0.96, p = .01), MR-PRESSO (OR = 0.85, 95% CI: 0.75-0.97, p = .02) and MR.RAPS (OR = 0.86, 95% CI: 0.76-0.98, p = .02) method showed that UC is associated with the risk of ICH. The causal relationship between IBD, CD, and the risk of ICH cannot be found by the IVW method. IBD and its subtypes UC, CD, and risk of ICH cannot find the presence of heterogeneity and pleiotropy. In replication stage, IBD (OR = 0.74, 95% CI: 0.59-0.94, p = .0135) related to ICH, while the IVW approach did not establish a causal link in UC and CD. The meta-analysis still indicated that UC (OR = 0.83, 95% CI: 0.72-0.93, p < .05) would lessen the risk of ICH while the causality between IBD, CD, and ICH was unable to be established. UC was causally related to ICH, but IBD and CD are not associated with ICH. The precise pathophysiological mechanism needs to be thoroughly investigated in more detail.

Association between gut microbiome and intracerebral hemorrhage based on genome-wide association study data.

Intracerebral hemorrhage (ICH) has the highest mortality and disability rates among various subtypes of stroke. Previous studies have shown that the gut microbiome (GM) is closely related to the risk factors and pathological basis of ICH. This study aims to explore the causal effect of GM on ICH and the potential mechanisms. Genome wide association study (GWAS) data on GM and ICH were obtained from Microbiome Genome and International Stroke Genetics Consortium. Based on the GWAS data, we first performed Mendelian randomization (MR) analysis to evaluate the causal association between GM and ICH. Then, a conditional false discovery rate (cFDR) method was conducted to identify the pleiotropic variants. MR analysis showed that Pasteurellales, Pasteurellaceae, and Haemophilus were negatively correlated with the risk of ICH, whileVerrucomicrobiae, Verrucomicrobiales, Verrucomicrobiaceae, Akkermansia, Holdemanella, and LachnospiraceaeUCG010 were positively correlated with ICH. By applying the cFDR method, 3 pleiotropic loci (rs331083, rs4315115, and rs12553325) were found to be associated with both GM and ICH. There is a causal association and pleiotropic variants between GM and ICH.

Association Between Prekallikrein and Stroke: A Mendelian Randomization Study.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P=5.44×10-5), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P=1.42×10-5), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P=3.75×10-4), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P=3.02×10-5). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

Genetic Causal Association Between the Gut Microbiome and Intracranial Aneurysm and Subarachnoid Hemorrhage: A Two-Sample Mendelian Randomization Study.

The causal association between the gut microbiome and the risk of intracranial aneurysm (IA), subarachnoid hemorrhage (SAH), and unruptured aneurysm (uIA) is unclear. The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary-level datasets of IA and SAH were obtained from the GWAS meta-analysis of the International Stroke Genetics Consortium (ISGC). Inverse variance weighting (IVW) was utilized as the primary method, complemented with sensitivity analyses for pleiotropy and increasing robustness. Five, seven, and six bacterial traits were found to have a causal effect on IA, SAH, and uIA, respectively (IVW, all P < 0.05). Family.Porphyromonadaceae and genus.Bilophila were common protective bacterial features for both SAH and uIA. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results. Our study demonstrates that gut microbiomes may exert therapeutic effects on IA, uIA, and SAH, providing clinical implications for the development of novel biomarkers and therapeutic targets.

Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study

BackgroundExperimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes.MethodsA total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes.ResultsGenetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01–1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01–1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02–1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03–1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings.ConclusionsWe found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.

Stroke and the risk of gastrointestinal disorders: A Mendelian randomization study.

The issue of whether a stroke is causally related to gastrointestinal disorders was still not satisfactorily understood. Therefore, we investigated if there is a connection between stroke and the most prevalent gastrointestinal disorders, including peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). We applied two-sample Mendelian randomization to investigate relationships with gastrointestinal disorders. We obtained genome-wide association study (GWAS) summary data of any stroke, ischemic stroke, and its subtypes from the MEGASTROKE consortium. From the International Stroke Genetics Consortium (ISGC) meta-analysis, we acquired GWAS summary information on intracerebral hemorrhage (ICH), including all ICH, deep ICH, and lobar ICH. Several sensitivity studies were performed to identify heterogeneity and pleiotropy, while inverse-variance weighted (IVW) was utilized as the most dominant estimate. No evidence for an effect of genetic predisposition to ischemic stroke and its subtypes on gastrointestinal disorders were found in IVW. The complications of deep ICH are a higher risk for PUD and GERD. Meanwhile, lobar ICH has a higher risk of complications for PUD. This study provides proof of the presence of a brain-gut axis. Among the complications of ICH, PUD and GERD were more common and associated with the site of hemorrhage.

Effects of blood lipids and lipid-modifying drugs on intracranial aneurysms.

We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-modifying drugs on intracranial aneurysm (IA). Genetic variants for the effects of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, and triglycerides and targets for lipid-modifying drugs were selected from the genome-wide discovery analyses of the UK Biobank. Summary-level data on IAs were obtained from the International Stroke Genetics Consortium. Univariate and multivariate MR analyses were performed. Univariate MR analyses showed that the HDL-C was negatively correlated with IA (odds ratio [OR] = 0.816, 95% confidence interval [CI] = 0.715-0.932, p= 0.003) and ruptured IA (rIA; OR=0.775, 95% CI=0.663-0.906, p= 0.001). The multivariate MR-inverse variance weighted analysis showed that the HDL-C was negatively correlated with IA (OR=0.655, 95% CI=0.434-0.988, p= 0.043) and rIA (OR=0.563, 95% CI=0.347-0.913, p= 0.02), and the LDL-C was negatively correlated with IA (OR=0.402, 95% CI=0.191-0.848, p= 0.017) and rIA (OR=0.376, 95% CI=0.160-0.883, p= 0.025). Using genetic proxies of known lipid-modifying drugs, we found that the increased HDL-C with cholesterol ester transfer protein proxies was associated with a decreased risk of rIA (OR=0.852, 95% CI=0.747-0.973, p= 0.018), and the decreased LDL-C with 3-hydroxy-3-methylglutaryl-coenzyme A reductase proxies was associated with increased risk of IA (OR=1.772, 95% CI=1.080-2.908, p= 0.024) and rIA (OR=1.856, 95% CI=1.022-3.371, p= 0.042). Genetically determined HDL-C and LDL-C reduce the risk of IA and rIA. The effects of different lipid-modifying drugs on IA need to be further investigated.

Evaluating the Causal Effects of TIMP-3 on Ischaemic Stroke and Intracerebral Haemorrhage: A Mendelian Randomization Study

Aim: Since tissue inhibitors of matrix metalloproteinase 3 (TIMP-3) was reported to be a potential risk factor of atherosclerosis, aneurysm, hypertension, and post-ischaemic neuronal injury, it may also be a candidate risk factor of stress. Therefore, this study was designed to explore the causal role of TIMP-3 in the risk of ischaemic stroke (IS) and intracerebral haemorrhage (ICH), which are the two main causes of stress via this Mendelian Randomisation (MR) study. Methods: The summarised data of TIMP-3 level in circulation was acquired from the Cooperative Health Research in the Region of Augsburg public database and the outcome of IS and ICH was obtained from genome-wide association studies conducted by MEGASTROKE and the International Stroke Genetics Consortium, respectively. Five statistical methods including inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test, and MR-Robust Adjusted Profile Score were applied to evaluate the causal role of TIMP-3 in the occurrence of IS and ICH. Inverse-variance weighting was applied for assessing causality. Furthermore, heterogeneity and pleiotropic tests were utilised to confirm the reliability of this study. Results: We found that TIMP-3 could be a positively causal relationship with the incidence of IS (OR = 1.026, 95% CI: 1.007–1.046, p = 0.0067), especially for the occurrence of small vessel stroke (SVS; OR = 1.045, 95% CI: 1.016–1.076, p = 0.0024). However, the causal effects of TIMP-3 on another IS subtype cardioembolic stroke (CES; OR = 1.049, 95% CI: 1.006–1.094, p = 0.024), large artery stroke (LAS; OR = 1.0027, 95% CI: 0.9755–1.0306, p = 0.849) and ICH (OR = 0.9900, 95% CI: 0.9403–1.0423, p = 0.701), as well as ICH subtypes were not observed after Bonferroni corrections (p = 0.00714). Conclusion: Our results revealed that high levels of circulating TIMP-3 causally increased the risk of developing IS and SVS, but not CES, LAS, ICH, and all ICH subtypes. Further investigation is required to elucidate the underlying mechanism.

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Abstract WMP80: Pleiotropy Analyses Of Between Intracerebral Hemorrhage And β-amyloid Related Phenotypes

Introduction: Combining biologically related traits in genome-wide association studies has been demonstrated to increase the power for genetic discovery and to identify new genes associated with intracerebral hemorrhage (ICH). Given the pathological relationship between lobar ICH and cerebral amyloid angiopathy (CAA), and between the latter and levels of CSF amyloid-β 42 (CSF-Aβ 42 ), we leveraged genetic predisposition for lower CSF Aβ 42 levels, as a proxy phenotype for CAA, in pleiotropy analysis for lobar ICH. Methods: We used publicly available GWAS data for Aβ 42 levels (n=3,146) and for lobar ICH (n=1,813) from the International Stroke Genetics Consortium. To evaluate the association between lobar ICH risk and CSF-Aβ 42 , we computed a polygenic risk score (PRS) for CSF-Aβ 42 in lobar ICH patients. We then applied multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aβ 42 . Gene-level associations based on the MTAG result were further tested using S-Predixcan. Results: We found a significant association between CSF-Aβ 42 PRS and ICH risk (β = -0.35; P = 0.04). MTAG analyses identified one novel near-genome-wide significant association within CDH9 (rs1007589; minor allele frequency=0.09; MTAG β = -0.12 and P = 5.4x10 -8 ; lobar ICH β = 0.34 and P = 2.4x10 -3 ; CSF-Aβ 42 β = -0.03 and P = 4.5x10 -6 ). According to the BRAINEAC brain tissue gene expression database, rs1007589 is significantly associated with increased expression of CDH9 in both temporal and occipital cortices. Discussion: This pleiotropy analysis was designed to identify genetic determinants of lobar ICH driven by amyloid-related mechanisms. We identified a variant in one novel gene associated with both traits, CDH9 , which causes differential expression in two brain regions characteristically affected by vascular amyloid pathology. CDH9 encodes for one subtype of the cadherin superfamily, which regulates intercellular adhesion. Cadherins have been involved in blood-brain barrier integrity and are elevated in AD patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.

Genetically determined risk of mood swings and cardiometabolic diseases: mendelian randomization study

Abstract Background Mood swings is believed to associated with increased risk of Cardiometabolic Diseases (CMD). However, the roles of mood swings on CMD are controversial because of the bias of reverse causation and/or confounding in epidemiological studies. Hence, we use a two-sample MR approach to identify the causal association between genetically determined mood swings and CMD. Methods We obtained 33 independent single-nucleotide polymorphisms (SNPs) with genome-wide significant (P&amp;lt;5×10–8) associated with mood swings as instrumental variable in UK Biobank. Summary data of outcomes were extracted from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics consortium, the Diabetes Genetics Replication and Meta-analysis consortium, the CKDGen consortium, and the International Stroke Genetics Consortium. Results The genetic instrument of 33 SNPs explained 4.8% of the variance in mood swings. Genetically determined mood swings was associated with an increased risk of coronary artery disease (CAD) (odds ratio 3.12, 95% confidence interval 1.92 to 5.08; P=4.32×10–6). However, mood swings had no effect on the other cardiometabolic outcomes. The above estimates were consistent across all three MR methods without significant heterogeneity. Also, there was no evidence of directional pleiotropy for each outcome except for large artery stroke. Conclusions Using MR approaches that are able draw causal inference, our results suggest that interventions aimed at improving mood swings in the population would lead to a reduction risk of CAD, which highlights the importance of mood management in high-risk CAD population. Funding Acknowledgement Type of funding sources: None.

International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery.

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

SummaryBackgroundThe genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.MethodsWe did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation.FindingsOur meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke.InterpretationLacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk.FundingBritish Heart Foundation.

Identifying novel genetic risk loci for lacunar stroke

In The Lancet Neurology, Matthew Traylor and colleagues 1 Traylor M Persyn E Tomppo L et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021; (published online March 25.)https://doi.org/10.1016/S1474-4422(21)00031-4 Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar report the results of the largest pooled analysis of risk genes for lacunar stroke published to date. The authors included more than 7000 patients with lacunar stroke and 250 000 controls. In almost 3000 cases, MRI confirmed the presence of lacunar stroke. Patients were recruited from the UK DNA Lacunar Stroke studies 1 and 2 and by the collaborators of the International Stroke Genetics Consortium. The authors did a genome-wide association study (GWAS) for lacunar stroke alone, as well as a multi-trait approach with a phenotype including both lacunar strokes and white matter hyperintensities. They also did a transcriptome-wide association study, which identified transcribed genes related to lacunar stroke. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studiesLacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Full-Text PDF Open Access