Publications by authors named "Rainer Malik"

132 Publications

Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease: A Mendelian Randomization Study.

Neurology 2021 Nov 29. Epub 2021 Nov 29.

Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.

Objective-: Cardiovascular risk factors have been implicated in the etiology of Cerebral Small Vessel Disease (CSVD), however whether the associations are causal remains unclear in part due to the susceptibility of observational studies to reverse causation and confounding. Here we use Mendelian randomization (MR) to determine which cardiovascular risk factors are likely to be involved in the etiology of CSVD.

Methods-: We used data from large scale genome-wide association studies (GWAS) of European ancestry to identify genetic proxies for blood pressure, blood lipids, body mass index (BMI), type-II diabetes, smoking initiation, cigarettes per day and alcohol consumption. MR was performed to assess their association with three neuroimaging features which are altered in CSVD (white matter hyperintensities (WMH), fractional anisotropy (FA) and mean diffusivity (MD)) using genetic summary data from UK Biobank (N=31,855). Our primary analysis used inverse-weighted median (IVW) MR, with validation using weighted median, MR-Egger and a pleiotropy-minimizing approach. Finally, multivariable MR was performed to study the effects of multiple risk factors jointly.

Results-: MR analysis showed consistent associations across all methods for higher genetically proxied systolic and diastolic blood pressure with WMH, FA, and MD; and for higher genetically proxied BMI with WMH. There was weaker evidence for associations between total cholesterol, LDL, smoking initiation, pulse pressure and type-II diabetes liability and at least one CSVD imaging feature, but these associations were not reproducible across all validation methods used. Multivariable MR analysis for blood pressure traits found that the effect was primarily through genetically proxied diastolic blood pressure across all CSVD traits.

Conclusion-: Genetic predisposition to higher blood pressure, primarily diastolic blood pressure, and higher BMI is associated with a higher burden of CSVD, suggesting a causal role. Improved management and treatment of these risk factors could reduce the burden of CSVD.
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http://dx.doi.org/10.1212/WNL.0000000000013120DOI Listing
November 2021

Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities.

Brain 2021 Oct;144(9):2670-2682

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany.

White matter hyperintensities (WMH) are among the most common radiological abnormalities in the ageing population and an established risk factor for stroke and dementia. While common variant association studies have revealed multiple genetic loci with an influence on their volume, the contribution of rare variants to the WMH burden in the general population remains largely unexplored. We conducted a comprehensive analysis of this burden in the UK Biobank using publicly available whole-exome sequencing data (n up to 17 830) and found a splice-site variant in GBE1, encoding 1,4-alpha-glucan branching enzyme 1, to be associated with lower white matter burden on an exome-wide level [c.691+2T>C, β = -0.74, standard error (SE) = 0.13, P = 9.7 × 10-9]. Applying whole-exome gene-based burden tests, we found damaging missense and loss-of-function variants in HTRA1 (frequency of 1 in 275 in the UK Biobank population) to associate with an increased WMH volume (P = 5.5 × 10-6, false discovery rate = 0.04). HTRA1 encodes a secreted serine protease implicated in familial forms of small vessel disease. Domain-specific burden tests revealed that the association with WMH volume was restricted to rare variants in the protease domain (amino acids 204-364; β = 0.79, SE = 0.14, P = 9.4 × 10-8). The frequency of such variants in the UK Biobank population was 1 in 450. The WMH volume was brought forward by ∼11 years in carriers of a rare protease domain variant. A comparison with the effect size of established risk factors for WMH burden revealed that the presence of a rare variant in the HTRA1 protease domain corresponded to a larger effect than meeting the criteria for hypertension (β = 0.26, SE = 0.02, P = 2.9 × 10-59) or being in the upper 99.8% percentile of the distribution of a polygenic risk score based on common genetic variants (β = 0.44, SE = 0.14, P = 0.002). In biochemical experiments, most (6/9) of the identified protease domain variants resulted in markedly reduced protease activity. We further found EGFL8, which showed suggestive evidence for association with WMH volume (P = 1.5 × 10-4, false discovery rate = 0.22) in gene burden tests, to be a direct substrate of HTRA1 and to be preferentially expressed in cerebral arterioles and arteries. In a phenome-wide association study mapping ICD-10 diagnoses to 741 standardized Phecodes, rare variants in the HTRA1 protease domain were associated with multiple neurological and non-neurological conditions including migraine with aura (odds ratio = 12.24, 95%CI: 2.54-35.25; P = 8.3 × 10-5]. Collectively, these findings highlight an important role of rare genetic variation and the HTRA1 protease in determining WMH burden in the general population.
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http://dx.doi.org/10.1093/brain/awab253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557338PMC
October 2021

The BS variant of C4 protects against age-related loss of white matter microstructural integrity.

Brain 2021 Aug 6. Epub 2021 Aug 6.

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.

Age-related loss of white matter microstructural integrity is a major determinant of cognitive decline, dementia, and gait disorders. However, the mechanisms and molecular pathways that contribute to this loss of integrity remain elusive. We performed a GWAS of white matter microstructural integrity as quantified by diffusion MRI metrics (mean diffusivity, MD; and fractional anisotropy, FA) in up to 31,128 individuals from UK Biobank (age 45-81 years) based on a 2 degrees of freedom (2df) test of single nucleotide polymorphism (SNP) and SNP x age effects. We identified 18 loci that were associated at genome-wide significance with either MD (N = 16) or FA (N = 6). Among the top loci was a region on chromosome 6 encoding the human major histocompatibility complex (MHC). Variants in the MHC region were strongly associated with both MD (best SNP: 6:28866209_TTTTG_T, beta(SE)=-0.069(0.009); 2df p = 6.5x10-15) and FA (best SNP: rs3129787, beta(SE)=-0.056(0.008); 2df p = 3.5x10-12). Of the imputed HLA alleles and complement component 4 (C4) structural haplotype variants in the human MHC, the strongest association was with the C4-BS variant (for MD: beta(SE)=-0.070(0.010); p = 2.7x10-11; for FA: beta(SE)=-0.054(0.011); p = 1.6x10-7). After conditioning on C4-BS no associations with HLA alleles remained significant. The protective influence of C4-BS was stronger in older subjects (age ≥ 65; interaction p = 0.0019 (MD), p = 0.015 (FA)) and in subjects without a history of smoking (interaction p = 0.00093 (MD), p = 0.021 (FA)). Taken together, our findings demonstrate a role of the complement system and of gene-environment interactions in age-related loss of white matter microstructural integrity.
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http://dx.doi.org/10.1093/brain/awab261DOI Listing
August 2021

KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease.

Nat Commun 2021 06 22;12(1):3825. Epub 2021 Jun 22.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany.

Klotho-VS heterozygosity (KL-VS) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VS is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VS and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VS showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VS on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VS was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VS carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VS against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia.
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http://dx.doi.org/10.1038/s41467-021-23755-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219708PMC
June 2021

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease.

Circulation 2021 Aug 18;144(5):353-364. Epub 2021 Jun 18.

Department of Surgery (V.M.W., S.M.D.), University of Pennsylvania Perelman School of Medicine, Philadelphia.

Background: Lipoprotein-related traits have been consistently identified as risk factors for atherosclerotic cardiovascular disease, largely on the basis of studies of coronary artery disease (CAD). The relative contributions of specific lipoproteins to the risk of peripheral artery disease (PAD) have not been well defined. We leveraged large-scale genetic association data to investigate the effects of circulating lipoprotein-related traits on PAD risk.

Methods: Genome-wide association study summary statistics for circulating lipoprotein-related traits were used in the mendelian randomization bayesian model averaging framework to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified with transcriptome-wide association studies.

Results: ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability, 0.86; =0.003) and CAD (marginal inclusion probability, 0.92; =0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio,0.87 per 1-SD decrease in ApoB [95% CI, 0.84-0.91]; =9×10) and CAD (odds ratio,0.66 [95% CI, 0.63-0.69]; =4×10), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09 [95% CI, 2.29-4.60]; <1×10). Extra-small very-low-density lipoprotein particle concentration was identified as the most likely subfraction associated with PAD risk (marginal inclusion probability, 0.91; =2.3×10), whereas large low-density lipoprotein particle concentration was the most likely subfraction associated with CAD risk (marginal inclusion probability, 0.95; =0.011). Genes associated with extra-small very-low-density lipoprotein particle and large low-density lipoprotein particle concentration included canonical ApoB pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD independently of ApoB (odds ratio, 1.04 [95% CI, 1.03-1.04]; =1.0×10).

Conclusions: ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.053797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323712PMC
August 2021

Circulating biomarkers of immunity and inflammation, risk of Alzheimer's disease, and hippocampal volume: a Mendelian randomization study.

Transl Psychiatry 2021 05 17;11(1):291. Epub 2021 May 17.

Institute for Stroke and Dementia Research, University Hospital LMU Munich, Munich, Germany.

The aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer's disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer's Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.
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http://dx.doi.org/10.1038/s41398-021-01400-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129147PMC
May 2021

Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank.

Alzheimers Dement 2021 09 22;17(9):1422-1431. Epub 2021 Mar 22.

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany.

Introduction: Midlife clustering of vascular risk factors has been associated with late-life dementia, but causal effects of individual biological and lifestyle factors remain largely unknown.

Methods: Among 229,976 individuals (mean follow-up 9 years), we explored whether midlife cardiovascular health measured by Life's Simple 7 (LS7) is associated with incident all-cause dementia and whether the individual components of the score are causally associated with dementia.

Results: Adherence to the biological metrics of LS7 (blood pressure, cholesterol, glycemic status) was associated with lower incident dementia risk (hazard ratio = 0.93 per 1-point increase, 95% confidence interval [CI; 0.89-0.96]). In contrast, there was no association between the composite LS7 score and the lifestyle subscore (smoking, body mass index, diet, physical activity) and incident dementia. In Mendelian randomization analyses, genetically elevated blood pressure was associated with higher risk of dementia (odds ratio = 1.31 per one-standard deviation increase, 95% CI [1.05-1.60]).

Discussion: These findings underscore the importance of blood pressure control in midlife to mitigate dementia risk.
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http://dx.doi.org/10.1002/alz.12320DOI Listing
September 2021

Genetically Downregulated Interleukin-6 Signaling Is Associated With a Favorable Cardiometabolic Profile: A Phenome-Wide Association Study.

Circulation 2021 Mar 15;143(11):1177-1180. Epub 2021 Mar 15.

Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany (M.K.G., R.M., M.D.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052604DOI Listing
March 2021

Simple and reliable detection of CRISPR-induced on-target effects by qgPCR and SNP genotyping.

Nat Protoc 2021 03 17;16(3):1714-1739. Epub 2021 Feb 17.

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany.

The recent CRISPR revolution has provided researchers with powerful tools to perform genome editing in a variety of organisms. However, recent reports indicate widespread occurrence of unintended CRISPR-induced on-target effects (OnTEs) at the edited site in mice and human induced pluripotent stem cells (iPSCs) that escape standard quality controls. By altering gene expression of targeted or neighbouring genes, OnTEs can severely affect phenotypes of CRISPR-edited cells and organisms and thus lead to data misinterpretation, which can undermine the reliability of CRISPR-based studies. Here we describe a broadly applicable framework for detecting OnTEs in genome-edited cells and organisms after non-homologous end joining-mediated and homology-directed repair-mediated editing. Our protocol enables identification of OnTEs such as large deletions, large insertions, rearrangements or loss of heterozygosity (LOH). This is achieved by subjecting genomic DNA first to quantitative genotyping PCR (qgPCR), which determines the number of intact alleles at the target site using the same PCR amplicon that has been optimized for genotyping. This combination of genotyping and quantitation makes it possible to exclude clones with monoallelic OnTEs and hemizygous editing, which are often mischaracterized as correctly edited in standard Sanger sequencing. Second, occurrence of LOH around the edited locus is detected by genotyping neighbouring single-nucleotide polymorphisms (SNPs), using either a Sanger sequencing-based method or SNP microarrays. All steps are optimized to maximize simplicity and minimize cost to promote wide dissemination and applicability across the field. The entire protocol from genomic DNA extraction to OnTE exclusion can be performed in 6-9 d.
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http://dx.doi.org/10.1038/s41596-020-00481-2DOI Listing
March 2021

Modifiable Lifestyle Factors and Risk of Stroke: A Mendelian Randomization Analysis.

Stroke 2021 03 4;52(3):931-936. Epub 2021 Feb 4.

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, United Kingdom (E.L.H., H.S.M.).

Background And Purpose: Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. We evaluated whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischemic stroke and its subtypes and hemorrhagic stroke.

Methods: We performed 2-sample and multivariable Mendelian randomization to assess the causal effect of 12 lifestyle factors on risk of stroke and whether these effects are independent.

Results: Genetically predicted years of education was inversely associated with ischemic, large artery, and small vessel stroke, and intracerebral hemorrhage. Genetically predicted smoking, body mass index, and waist-hip ratio were associated with ischemic and large artery stroke. The effects of education, body mass index, and smoking on ischemic stroke were independent.

Conclusions: Our findings support the hypothesis that reduced education and increased smoking and obesity increase risk of ischemic, large artery, and small vessel stroke, suggesting that lifestyle modifications addressing these risk factors will reduce stroke risk.
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http://dx.doi.org/10.1161/STROKEAHA.120.031710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903981PMC
March 2021

Dose-response relationship between genetically proxied average blood glucose levels and incident coronary heart disease in individuals without diabetes mellitus.

Diabetologia 2021 04 26;64(4):845-849. Epub 2021 Jan 26.

Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, UK.

Aims/hypothesis: Our aim was to investigate the relationship between average blood glucose levels and incident CHD in individuals without diabetes mellitus.

Methods: To investigate average blood glucose levels, we studied HbA as predicted by 40 variants previously shown to be associated with both type 2 diabetes and HbA. Linear and non-linear Mendelian randomisation analyses were performed to investigate associations with incident CHD risk in 324,830 European ancestry individuals from the UK Biobank without diabetes mellitus.

Results: Every one mmol/mol increase in genetically proxied HbA was associated with an 11% higher CHD risk (HR 1.11, 95% CI 1.05, 1.18). The dose-response curve increased at all levels of HbA, and there was no evidence favouring a non-linear relationship over a linear one.

Conclusions/interpretations: In individuals without diabetes mellitus, lowering average blood glucose levels may reduce CHD risk in a dose-dependent way.
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http://dx.doi.org/10.1007/s00125-020-05377-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940279PMC
April 2021

Diabetes Mellitus, Glycemic Traits, and Cerebrovascular Disease: A Mendelian Randomization Study.

Neurology 2021 03 25;96(13):e1732-e1742. Epub 2021 Jan 25.

From the Institute for Stroke and Dementia Research (M.K.G., R.M., M.D.), Department of Neurology (M.K.G), University Hospital, and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Stroke Research Group, Department of Clinical Neurosciences (E.L.H., H.S.M.), and MRC Epidemiology Unit (C.L., N.J.W.), University of Cambridge, UK; Department of Epidemiology (N.F.), UNC Gillings Global School of Public Health, Chapel Hill, NC; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore the effects of genetic predisposition to type 2 diabetes (T2D), hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction on risk of stroke subtypes and related cerebrovascular phenotypes.

Methods: We selected instruments for genetic predisposition to T2D (74,124 cases, 824,006 controls), HbA1c levels (n = 421,923), fasting glucose levels (n = 133,010), insulin resistance (n = 108,557), and β-cell dysfunction (n = 16,378) based on published genome-wide association studies. Applying 2-sample Mendelian randomization, we examined associations with ischemic stroke (60,341 cases, 454,450 controls), intracerebral hemorrhage (1,545 cases, 1,481 controls), and ischemic stroke subtypes (large artery, cardioembolic, small vessel stroke), as well as with related phenotypes (carotid atherosclerosis, imaging markers of cerebral white matter integrity, and brain atrophy).

Results: Genetic predisposition to T2D and higher HbA1c levels were associated with higher risk of any ischemic stroke, large artery stroke, and small vessel stroke. Similar associations were also noted for carotid atherosclerotic plaque, fractional anisotropy, a white matter disease marker, and markers of brain atrophy. We further found associations of genetic predisposition to insulin resistance with large artery and small vessel stroke, whereas predisposition to β-cell dysfunction was associated with small vessel stroke, intracerebral hemorrhage, lower gray matter volume, and total brain volume.

Conclusions: This study supports causal effects of T2D and hyperglycemia on large artery and small vessel stroke. We show associations of genetically predicted insulin resistance and β-cell dysfunction with large artery and small vessel stroke that might have implications for antidiabetic treatments targeting these mechanisms.

Classification Of Evidence: This study provides Class II evidence that genetic predisposition to T2D and higher HbA1c levels are associated with a higher risk of large artery and small vessel ischemic stroke.
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http://dx.doi.org/10.1212/WNL.0000000000011555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055310PMC
March 2021

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

Multi-shell Diffusion MRI Models for White Matter Characterization in Cerebral Small Vessel Disease.

Neurology 2021 02 16;96(5):e698-e708. Epub 2020 Nov 16.

From the Institute for Stroke and Dementia Research (ISD) (M.J.K., A.D., B.G., S.F., A. Kopczak, M.H., R.M., M.E., M.D.) and the Department of Radiology (O.D.), University Hospital, LMU Munich, Germany; Department of Neurology (A.t.T., K.W., A.M.T., F.-E.d.L., M.D.) and Radboud University (J.P.M., D.G.N.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands;Population Health Sciences (A.K.), German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;Department of Neurology (R.S.), Medical University of Graz, Austria; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.

Objective: To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics.

Methods: We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners.

Results: Metrics from DKI showed the strongest associations with processing speed performance ( up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible.

Conclusion: Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies.

Classification Of Evidence: This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.
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http://dx.doi.org/10.1212/WNL.0000000000011213DOI Listing
February 2021

Detection of cytokine-induced sickness behavior after ischemic stroke by an optimized behavioral assessment battery.

Brain Behav Immun 2021 01 14;91:668-672. Epub 2020 Nov 14.

Institute for Stroke and Dementia Research (ISD), Klinikum der Universität München, 81377 Munich, Germany; Munich Cluster for System Neurology (SyNergy), 80336 Munich, Germany. Electronic address:

Stroke causes severe and long-lasting symptoms in patients. Besides focal deficits such as speech impairment and limb weakness, stroke also results in neuropsychiatric symptoms, including fatigue, anxiety, and depression, which are debilitating and often impair post-stroke rehabilitation. However, in experimental stroke research, the study of neuropsychiatric symptoms and their therapeutic targeting has so far been largely neglected, which can be mainly attributed to the lack of appropriate tools to investigate such deficits in mice. Here, we report that neuropsychiatric symptoms can be differentiated from focal deficits and specifically modulated independent of treating the primary lesion. In order to achieve this, we developed a novel behavior analysis tool by assessing test performance of various tests, combining outcome parameters to cover functional domains of focal and neuropsychiatric symptoms, and finally weighted results into a time point-specific score. This weighted score enabled us to clearly differentiate focal deficits and neuropsychiatric symptoms and detect these until the chronic phase after stroke. Using this analysis tool, we detected that neutralizing systemic cytokines (TNF-α, IL-1β and IL-6) specifically ameliorated neuropsychiatric symptoms but did not affect focal deficits or lesion volume. Hence, most conventional studies analyzing only focal deficits and lesion volume as primary outcome measures would have missed these significant and translationally relevant therapeutic effects. We anticipate that these findings will encourage more detailed analyses of neuropsychiatric symptoms particularly for anti-inflammatory therapies in stroke and that the presented weighted composite score will facilitate this development.
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http://dx.doi.org/10.1016/j.bbi.2020.11.016DOI Listing
January 2021

Complicated Carotid Artery Plaques as a Cause of Cryptogenic Stroke.

J Am Coll Cardiol 2020 11;76(19):2212-2222

Department of Radiology, University Hospital, LMU Munich, Munich, Germany; Radiologisches Zentrum Rosenheim, Rosenheim, Germany.

Background: The underlying etiology of ischemic stroke remains unknown in up to 30% of patients.

Objectives: This study explored the causal role of complicated (American Heart Association-lesion type VI) nonstenosing carotid artery plaques (CAPs) in cryptogenic stroke (CS).

Methods: CAPIAS (Carotid Plaque Imaging in Acute Stroke) is an observational multicenter study that prospectively recruited patients aged older than 49 years with acute ischemic stroke that was restricted to the territory of a single carotid artery on brain magnetic resonance imaging (MRI) and unilateral or bilateral CAP (≥2 mm, NASCET [North American Symptomatic Carotid Endarterectomy Trial] <70%). CAP characteristics were determined qualitatively and quantitatively by high-resolution, contrast-enhanced carotid MRI at 3T using dedicated surface coils. The pre-specified study hypotheses were that that the prevalence of complicated CAP would be higher ipsilateral to the infarct than contralateral to the infarct in CS and higher in CS compared with patients with cardioembolic or small vessel stroke (CES/SVS) as a combined reference group. Patients with large artery stroke (LAS) and NASCET 50% to 69% stenosis served as an additional comparison group.

Results: Among 234 recruited patients, 196 had either CS (n = 104), CES/SVS (n = 79), or LAS (n = 19) and complete carotid MRI data. The prevalence of complicated CAP in patients with CS was significantly higher ipsilateral (31%) to the infarct compared with contralateral to the infarct (12%; p = 0.0005). Moreover, the prevalence of ipsilateral complicated CAP was significantly higher in CS (31%) compared with CES/SVS (15%; p = 0.02) and lower in CS compared with LAS (68%; p = 0.003). Lipid-rich and/or necrotic cores in ipsilateral CAP were significantly larger in CS compared with CES/SVS (p < 0.05).

Conclusions: These findings substantiate the role of complicated nonstenosing CAP as an under-recognized cause of stroke. (Carotid Plaque Imaging in Acute Stroke [CAPIAS]; NCT01284933).
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http://dx.doi.org/10.1016/j.jacc.2020.09.532DOI Listing
November 2020

Association of Circulating Monocyte Chemoattractant Protein-1 Levels With Cardiovascular Mortality: A Meta-analysis of Population-Based Studies.

JAMA Cardiol 2021 May;6(5):587-592

Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-University, Munich, Germany.

Importance: Human genetics and studies in experimental models support a key role of monocyte-chemoattractant protein-1 (MCP-1) in atherosclerosis. Yet, the associations of circulating MCP-1 levels with risk of coronary heart disease and cardiovascular death in the general population remain largely unexplored.

Objective: To explore whether circulating levels of MCP-1 are associated with risk of incident coronary heart disease, myocardial infarction, and cardiovascular mortality in the general population.

Data Sources And Selection: Population-based cohort studies, identified through a systematic review, that have examined associations of circulating MCP-1 levels with cardiovascular end points.

Data Extraction And Synthesis: Using a prespecified harmonized analysis plan, study-specific summary data were obtained from Cox regression models after excluding individuals with overt cardiovascular disease at baseline. Derived hazard ratios (HRs) were synthesized using random-effects meta-analyses.

Main Outcomes And Measures: Incident coronary heart disease (myocardial infarction, coronary revascularization, and unstable angina), nonfatal myocardial infarction, and cardiovascular death (from cardiac or cerebrovascular causes).

Results: The meta-analysis included 7 cohort studies involving 21 401 individuals (mean [SD] age, 53.7 [10.2] years; 10 012 men [46.8%]). Mean (SD) follow-up was 15.3 (4.5) years (326 392 person-years at risk). In models adjusting for age, sex, and race/ethnicity, higher MCP-1 levels at baseline were associated with increased risk of coronary heart disease (HR per 1-SD increment in MCP-1 levels: 1.06 [95% CI, 1.01-1.11]; P = .01), nonfatal myocardial infarction (HR, 1.07 [95% CI, 1.01-1.13]; P = .02), and cardiovascular death (HR, 1.12 [95% CI, 1.05-1.20]; P < .001). In analyses comparing MCP-1 quartiles, these associations followed dose-response patterns. After additionally adjusting for vascular risk factors, the risk estimates were attenuated, but the associations of MCP-1 levels with cardiovascular death remained statistically significant, as did the association of MCP-1 levels in the upper quartile with coronary heart disease. There was no significant heterogeneity; the results did not change in sensitivity analyses excluding events occurring in the first 5 years after MCP-1 measurement, and the risk estimates were stable after additional adjustments for circulating levels of interleukin-6 and high-sensitivity C-reactive protein.

Conclusions And Relevance: Higher circulating MCP-1 levels are associated with higher long-term cardiovascular mortality in community-dwelling individuals free of overt cardiovascular disease. These findings provide further support for a key role of MCP-1-signaling in cardiovascular disease.
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http://dx.doi.org/10.1001/jamacardio.2020.5392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111478PMC
May 2021

Broad phenotype of cysteine-altering variants in UK Biobank: CADASIL to nonpenetrance.

Neurology 2020 09 30;95(13):e1835-e1843. Epub 2020 Jul 30.

From the Center for Hereditary Small Vessel Disease, Department of Clinical Genetics (J.W.R., R.J.H., G.G., J.G.D., S.A.J.L.O.), Department of Human Genetics (M.O.), Department of Biomedical Data Sciences (E.B.v.d.A.), and Department of Biomedical Data Sciences (E.S.), Leiden University Medical Center, the Netherlands; Institute for Stroke and Dementia Research (M.D., M.D., R.M.), University Hospital, LMU Munich, Germany; Pattern Recognition & Bioinformatics (E.B.v.d.A., H.H.), Delft University of Technology; Alzheimer Center Amsterdam (H.H.), Department of Neurology, Amsterdam Neuroscience, and Department of Clinical Genetics (H.H.), Vrije Universiteit Amsterdam, Amsterdam UMC, the Netherlands; and Department of Radiology and Imaging Sciences (K.N., A.S.), Indiana Alzheimer Disease Center, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis.

Objective: To determine the small vessel disease spectrum associated with cysteine-altering variants in community-dwelling individuals by analyzing the clinical and neuroimaging features of UK Biobank participants harboring such variants.

Methods: The exome and genome sequencing datasets of the UK Biobank (n = 50,000) and cohorts of cognitively healthy elderly (n = 751) were queried for cysteine-altering variants. Brain MRIs of individuals harboring such variants were scored according to Standards for Reporting Vascular Changes on Neuroimaging criteria, and clinical information was extracted with ICD-10 codes. Clinical and neuroimaging data were compared to age- and sex-matched UK Biobank controls and clinically diagnosed patients from the Dutch cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) registry.

Results: We identified 108 individuals harboring a cysteine-altering variant (2.2 of 1,000), of whom 75% have a variant that has previously been reported in CADASIL pedigrees. Almost all variants were located in 1 of the NOTCH3 protein epidermal growth factor-like repeat domains 7 to 34. White matter hyperintensity lesion load was higher in individuals with variants than in controls ( = 0.006) but lower than in patients with CADASIL with the same variants ( < 0.001). Almost half of the 24 individuals with brain MRI had a Fazekas score of 0 or 1 up to age 70 years. There was no increased risk of stroke.

Conclusions: Although community-dwelling individuals harboring a cysteine-altering variant have a higher small vessel disease MRI burden than controls, almost half have no MRI abnormalities up to age 70 years. This shows that cysteine altering variants are associated with an extremely broad phenotypic spectrum, ranging from CADASIL to nonpenetrance.
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http://dx.doi.org/10.1212/WNL.0000000000010525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682826PMC
September 2020

Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Stroke 2020 08 22;51(8):2454-2463. Epub 2020 Jul 22.

Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC (C.D.L., C.L.).

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 gene that reached genome-wide significance (=4.62×10) and an additional 29 variants with suggestive evidence of association (<1×10), 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 value of 2.08×10 (0.05/24 unique loci), we were able to validate associations at the locus in both SiGN (=8.18×10) and METASTROKE (=1.72×10) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the and 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.
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http://dx.doi.org/10.1161/STROKEAHA.120.029123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387190PMC
August 2020

Genetically Predicted Midlife Blood Pressure and Coronary Artery Disease Risk: Mendelian Randomization Analysis.

J Am Heart Assoc 2020 07 4;9(14):e016773. Epub 2020 Jul 4.

Institute for Stroke and Dementia Research University Hospital of Ludwig-Maximilians-University Munich Germany.

Background Elevated blood pressure is a major cause of cardiovascular morbidity and mortality. However, it is not known whether midlife blood pressure affects later life cardiovascular risk independent of later life blood pressure. Methods and Results Using genetic association estimates from the UK Biobank and CARDIoGRAMplusC4D consortium, univariable mendelian randomization was performed to investigate the total effect of genetically predicted mean arterial pressure (MAP) at age ≤55 years on coronary artery disease (CAD) risk, and multivariable mendelian randomization was performed to investigate the effect of genetically predicted MAP on CAD risk after adjusting for genetically predicted MAP at age >55 years. In both univariable and multivariable mendelian randomization analyses, there was consistent evidence of higher genetically predicted MAP at age ≤55 years increasing CAD risk. This association persisted after adjusting for genetically predicted MAP at age >55 years, when considering nonoverlapping populations for the derivation of MAP and CAD risk genetic association estimates, when investigating only incident CAD events after age >55 years, and when restricting the analysis to variants with most heterogeneity in their associations with MAP ≤55 and >55 years. For a 10-mm Hg increase in genetically predicted MAP at age ≤55 years, the odds ratio of later life CAD was 1.43 (95% CI, 1.16-1.77; =0.001) after adjusting for genetically predicted MAP at age >55 years. Conclusions These mendelian randomization findings support a cumulative lifetime effect of elevated blood pressure on increasing CAD risk. Clinical and public health efforts toward cardiovascular disease reduction should optimize blood pressure control throughout life.
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http://dx.doi.org/10.1161/JAHA.120.016773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660704PMC
July 2020

Genetically Predicted Blood Pressure Across the Lifespan: Differential Effects of Mean and Pulse Pressure on Stroke Risk.

Hypertension 2020 09 6;76(3):953-961. Epub 2020 Jul 6.

From the Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Germany (M.K.G., R.M., M.D.).

Hypertension is the leading risk factor for stroke. Yet, it remains unknown whether blood pressure pulsatility (pulse pressure [PP]) causally affects stroke risk independently of the steady pressure component (mean arterial pressure [MAP]). It is further unknown how the effects of MAP and PP on stroke risk vary with age and stroke cause. Using data from UK Biobank (N=408 228; 38-71 years), we selected genetic variants as instruments for MAP and PP at age ≤55 and >55 years and across age deciles. We applied multivariable Mendelian randomization analyses to explore associations with ischemic stroke, intracerebral hemorrhage, and their subtypes. Higher genetically predicted MAP was associated with higher risk of ischemic stroke and intracerebral hemorrhage across the examined age spectrum. Independent of MAP, higher genetically predicted PP only at age >55 years was further associated with higher risk of ischemic stroke (odds ratio per-SD-increment, 1.23 [95% CI, 1.13-1.34]). Among subtypes, the effect of genetically predicted MAP on large artery stroke was attenuated, whereas the effect of genetically predicted PP was augmented with increasing age. Genetically predicted MAP, but not PP, was associated with small vessel stroke and deep intracerebral hemorrhage homogeneously across age deciles. Neither genetically predicted MAP nor PP were associated with lobar intracerebral hemorrhage. Beyond an effect of high MAP at any age on ischemic and hemorrhagic stroke, our results support an independent causal effect of high PP at older ages on large artery stroke. This finding warrants further investigation for the development of stroke preventive strategies targeting pulsatility in later life.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418931PMC
September 2020

Genetically determined blood pressure, antihypertensive drug classes, and risk of stroke subtypes.

Neurology 2020 07 1;95(4):e353-e361. Epub 2020 Jul 1.

From the Institute for Stroke and Dementia Research (ISD), University Hospital (M.K.G., R.M., M.D.), and Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany; Department of Biostatistics and Epidemiology, School of Public Health (D.G., E.E., C.L.M.S., A.D., I.T.), UK Dementia Research Institute (P.E., A.D.), Health Data Research-UK London (P.E.), and MRC-PHE Centre for Environment, School of Public Health (I.T.), Imperial College London; Centre for Prevention of Stroke and Dementia, Department of Clinical Neurosciences (A.J.S.W.), University of Oxford, UK; Department of Hygiene and Epidemiology (E.E., I.T.), University of Ioannina Medical School, Greece; National Institute for Health Research Imperial College Biomedical Research Centre (P.E.), London; Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Munich Cluster for Systems Neurology (SyNergy) (M.D.); and German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany.

Objective: We employed Mendelian randomization to explore whether the effects of blood pressure (BP) and BP-lowering through different antihypertensive drug classes on stroke risk vary by stroke etiology.

Methods: We selected genetic variants associated with systolic and diastolic BP and BP-lowering variants in genes encoding antihypertensive drug targets from genome-wide association studies (GWAS) on 757,601 individuals. Applying 2-sample Mendelian randomization, we examined associations with any stroke (67,162 cases; 454,450 controls), ischemic stroke and its subtypes (large artery, cardioembolic, small vessel stroke), intracerebral hemorrhage (ICH, deep and lobar), and the related small vessel disease phenotype of white matter hyperintensities (WMH).

Results: Genetic predisposition to higher systolic and diastolic BP was associated with higher risk of any stroke, ischemic stroke, and ICH. We found associations between genetically determined BP and all ischemic stroke subtypes with a higher risk of large artery and small vessel stroke compared to cardioembolic stroke, as well as associations with deep, but not lobar ICH. Genetic proxies for calcium channel blockers, but not β-blockers, were associated with lower risk of any stroke and ischemic stroke. Proxies for calcium channel blockers showed particularly strong associations with small vessel stroke and the related radiologic phenotype of WMH.

Conclusions: This study supports a causal role of hypertension in all major stroke subtypes except lobar ICH. We find differences in the effects of BP and BP-lowering through antihypertensive drug classes between stroke subtypes and identify calcium channel blockade as a promising strategy for preventing manifestations of cerebral small vessel disease.
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http://dx.doi.org/10.1212/WNL.0000000000009814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455321PMC
July 2020

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability.

Circ Res 2020 08 17;127(6):811-823. Epub 2020 Jun 17.

From the Institute for Stroke and Dementia Research, University Hospital (Y.A., T.A.C.-J., Y.B., L.L.Y., M.P., O.E.B., S.R., K.T., G.Y., M.S., N.Z., S.T., Y.H., M.S., R.M., C.H., A.L., J.B., M.D.), Ludwig-Maximilians-University, Munich, Germany.

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of HDAC (histone deacetylase)-9 in atherosclerosis and its clinical complications including stroke and myocardial infarction.

Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection.

Methods And Results: We studied the effects of on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further used 2-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic deficiency reduces lesional macrophage content while increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKK (inhibitory kappa B kinase)-α and β, resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting proinflammatory responses in macrophages. Transcriptional profiling using RNA sequencing revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL (interleukin)-1β and IL-6.

Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation. Graphical Abstract: A graphical abstract is available for this article.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316743DOI Listing
August 2020

Common Genetic Variation Indicates Separate Causes for Periventricular and Deep White Matter Hyperintensities.

Stroke 2020 07 10;51(7):2111-2121. Epub 2020 Jun 10.

Department of Psychiatry (C.F.-N.), University of California, San Diego, La Jolla, CA.

Background And Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings.

Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC.

Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 (), 10q23.1 (), and 10q24.33 ( In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 () and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: (2q32.1), (3q27.1), (5q27.1), and (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype.

Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.
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http://dx.doi.org/10.1161/STROKEAHA.119.027544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365038PMC
July 2020

Detection of Deleterious On-Target Effects after HDR-Mediated CRISPR Editing.

Cell Rep 2020 05;31(8):107689

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany; Graduate School of Systemic Neurosciences, LMU Munich, 82152 Planegg-Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany. Electronic address:

CRISPR genome editing is a promising tool for translational research but can cause undesired editing outcomes, both on target at the edited locus and off target at other genomic loci. Here, we investigate the occurrence of deleterious on-target effects (OnTEs) in human stem cells after insertion of disease-related mutations by homology-directed repair (HDR) and gene editing using non-homologous end joining (NHEJ). We identify large, mono-allelic genomic deletions and loss-of-heterozygosity escaping standard quality controls in up to 40% of edited clones. To reliably detect such events, we describe simple, low-cost, and broadly applicable quantitative genotyping PCR (qgPCR) and single-nucleotide polymorphism (SNP) genotyping-based tools and suggest their usage as additional quality controls after editing. This will help to ensure the integrity of edited loci and increase the reliability of CRISPR editing.
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http://dx.doi.org/10.1016/j.celrep.2020.107689DOI Listing
May 2020

Genetic overlap and causal inferences between kidney function and cerebrovascular disease.

Neurology 2020 06 21;94(24):e2581-e2591. Epub 2020 May 21.

From the Center for Genomic Medicine (S.M., J.C., J.Q.A.H., J.R., C.D.A.), Department of Neurology (J.R., C.D.A.), and Henry and Allison McCance Center for Brain Health (J.R., C.D.A.), Massachusetts General Hospital, Boston; Institute for Stroke and Dementia Research (M.K.G., M.D., R.M.), University Hospital of Ludwig-Maximilians-University; Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-University, Munich, Germany; Department of Medicine (Biomedical Genetics) (J.C.), Boston University School of Medicine, MA; Munich Cluster for Systems Neurology (SyNergy) (M.D.); German Centre for Neurodegenerative Diseases (DZNE) (M.D.), Munich, Germany; and Program in Medical and Population Genetics (J.R., C.D.A.), Broad Institute of Harvard and MIT, Cambridge, MA.

Objective: Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes.

Methods: We used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease diagnosis, estimated glomerular filtration rate [eGFR], and urinary albumin-to-creatinine ratio [UACR]) and cerebrovascular disease phenotypes (ischemic stroke and its subtypes, intracerebral hemorrhage [ICH], and white matter hyperintensities [WMH] on brain MRI). We (1) tested the genetic overlap between them with polygenic risk scores (PRS), (2) searched for common pleiotropic loci with pairwise GWAS analyses, and (3) explored causal associations by employing 2-sample Mendelian randomization.

Results: A PRS for lower eGFR was associated with higher large artery stroke (LAS) risk ( = 1 × 10). Multiple pleiotropic loci were identified between kidney function traits and cerebrovascular disease phenotypes, with 12q24 associated with eGFR and both LAS and small vessel stroke (SVS), and 2q33 associated with UACR and both SVS and WMH. Mendelian randomization revealed associations of both lower eGFR (odds ratio [OR] per 1-log decrement, 2.10; 95% confidence interval [CI], 1.38-3.21) and higher UACR (OR per 1-log increment, 2.35; 95% CI, 1.12-4.94) with a higher risk of LAS, as well as between higher UACR and higher risk of ICH.

Conclusions: Impaired kidney function, as assessed by decreased eGFR and increased UACR, may be causally involved in the pathogenesis of LAS. Increased UACR, previously proposed as a marker of systemic small vessel disease, is involved in ICH risk and shares a genetic risk factor at 2q33 with manifestations of cerebral small vessel disease.
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http://dx.doi.org/10.1212/WNL.0000000000009642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455337PMC
June 2020

Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study.

Circ Genom Precis Med 2020 06 12;13(3):e002872. Epub 2020 May 12.

Institute for Stroke and Dementia Research (ISD) (M.K.G., R.M., M.D.), University Hospital, Ludwig-Maximilians-University LMU, Munich, Germany.

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http://dx.doi.org/10.1161/CIRCGEN.119.002872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299212PMC
June 2020

Author Correction: Genomic risk score offers predictive performance comparable to clinical risk factors for ischaemic stroke.

Nat Commun 2020 Feb 20;11(1):1036. Epub 2020 Feb 20.

Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität LMU, Munich, Germany.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-020-14717-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033171PMC
February 2020
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