Publications by authors named "Kristiina Rannikmae"

33 Publications

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

Alzheimers Dement 2021 Mar 22. 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
March 2021

Benchmarking network-based gene prioritization methods for cerebral small vessel disease.

Brief Bioinform 2021 Feb 26. Epub 2021 Feb 26.

Health Data Research UK, London, United Kingdom.

Network-based gene prioritization algorithms are designed to prioritize disease-associated genes based on known ones using biological networks of protein interactions, gene-disease associations (GDAs) and other relationships between biological entities. Various algorithms have been developed based on different mechanisms, but it is not obvious which algorithm is optimal for a specific disease. To address this issue, we benchmarked multiple algorithms for their application in cerebral small vessel disease (cSVD). We curated protein-gene interactions (PGIs) and GDAs from databases and assembled PGI networks and disease-gene heterogeneous networks. A screening of algorithms resulted in seven representative algorithms to be benchmarked. Performance of algorithms was assessed using both leave-one-out cross-validation (LOOCV) and external validation with MEGASTROKE genome-wide association study (GWAS). We found that random walk with restart on the heterogeneous network (RWRH) showed best LOOCV performance, with median LOOCV rediscovery rank of 185.5 (out of 19 463 genes). The GenePanda algorithm had most GWAS-confirmable genes in top 200 predictions, while RWRH had best ranks for small vessel stroke-associated genes confirmed in GWAS. In conclusion, RWRH has overall better performance for application in cSVD despite its susceptibility to bias caused by degree centrality. Choice of algorithms should be determined before applying to specific disease. Current pure network-based gene prioritization algorithms are unlikely to find novel disease-associated genes that are not associated with known ones. The tools for implementing and benchmarking algorithms have been made available and can be generalized for other diseases.
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http://dx.doi.org/10.1093/bib/bbab006DOI Listing
February 2021

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

Nat Genet 2021 Feb;53(2):254

Department of Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.

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http://dx.doi.org/10.1038/s41588-020-00760-4DOI Listing
February 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 Neurology and Neurosurgery, University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands.

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

Beyond the Brain: Systematic Review of Extracerebral Phenotypes Associated With Monogenic Cerebral Small Vessel Disease.

Stroke 2020 10 26;51(10):3007-3017. Epub 2020 Aug 26.

Centre for Medical Informatics, Usher Institute (K.R., D.E.H., T.W., K.W., C.S.), University of Edinburgh, United Kingdom.

Background And Purpose: An important minority of cerebral small vessel disease (cSVD) is monogenic. Many monogenic cSVD genes are recognized to be associated with extracerebral phenotypes. We assessed the frequency of these phenotypes in existing literature.

Methods: We performed a systematic review following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), searching Medline/Embase for publications describing individuals with pathogenic variants in , , , , and genes (PROSPERO 74804). We included any publication reporting on ≥1 individual with a pathogenic variant and their clinically relevant phenotype. We extracted individuals' characteristics and information about associated extracerebral phenotypes and stroke/transient ischemic attack. We noted any novel extracerebral phenotypes and looked for shared phenotypes between monogenic cSVDs.

Results: After screening 6048 publications, we included 96 (350 individuals), 32 (115 individuals), 43 (38 homozygous/61 heterozygous individuals), 16 (37 individuals), 119 (209 individuals), and 3 (14 individuals) publications. The majority of individuals originated from Europe/North America, except for , where most were from Asia. Age varied widely, individuals being youngest and heterozygous individuals oldest. Sex distribution appeared equal. Extracerebral phenotypes were common: 14% to 100% of individuals with a pathogenic variant manifested at least one extracerebral phenotype (14% , 43% heterozygotes, 47% , 57% , 91% , 94% homozygotes, and 100% individuals). Indeed, for 4 of 7 genes, an extracerebral phenotype was observed more frequently than stroke/transient ischemic attack. Ocular, renal, hepatic, muscle, and hematologic systems were each involved in more than one monogenic cSVD.

Conclusions: Extracerebral phenotypes are common in monogenic cSVD with extracerebral system involvement shared between genes. However, inherent biases in the existing literature mean that further data from large-scale population-based longitudinal studies collecting health outcomes in a systematic unbiased way is warranted. The emerging knowledge will help to select patients for testing, inform clinical management, and provide further insights into the underlying mechanisms of cSVD.
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http://dx.doi.org/10.1161/STROKEAHA.120.029517DOI Listing
October 2020

Accuracy of identifying incident stroke cases from linked health care data in UK Biobank.

Neurology 2020 08 2;95(6):e697-e707. Epub 2020 Jul 2.

From the Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics (K.R., K.B., R.F., A.H., J.N., C.S., T.W., K.W., Q.Z., C.L.M.S.), and Centre for Clinical Brain Sciences (R.A.-S.S., F.D., N.S., W.W., R.W.), University of Edinburgh; UK Biobank (K.R., K.B., R.F., A.H., J.N., C.S., T.W., K.W., R.W., Q.Z., N.A., C.L.M.S.), Stockport; University of Edinburgh Medical School (K.N., D.E.H., S.O.); and Nuffield Department of Population Health (N.A.), University of Oxford, UK.

Objective: In UK Biobank (UKB), a large population-based prospective study, cases of many diseases are ascertained through linkage to routinely collected, coded national health datasets. We assessed the accuracy of these for identifying incident strokes.

Methods: In a regional UKB subpopulation (n = 17,249), we identified all participants with ≥1 code signifying a first stroke after recruitment (incident stroke-coded cases) in linked hospital admission, primary care, or death record data. Stroke physicians reviewed their full electronic patient records (EPRs) and generated reference standard diagnoses. We evaluated the number and proportion of cases that were true-positives (i.e., positive predictive value [PPV]) for all codes combined and by code source and type.

Results: Of 232 incident stroke-coded cases, 97% had EPR information available. Data sources were 30% hospital admission only, 39% primary care only, 28% hospital and primary care, and 3% death records only. While 42% of cases were coded as unspecified stroke type, review of EPRs enabled a pathologic type to be assigned in >99%. PPVs (95% confidence intervals) were 79% (73%-84%) for any stroke (89% for hospital admission codes, 80% for primary care codes) and 83% (74%-90%) for ischemic stroke. PPVs for small numbers of death record and hemorrhagic stroke codes were low but imprecise.

Conclusions: Stroke and ischemic stroke cases in UKB can be ascertained through linked health datasets with sufficient accuracy for many research studies. Further work is needed to understand the accuracy of death record and hemorrhagic stroke codes and to develop scalable approaches for better identifying stroke types.
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http://dx.doi.org/10.1212/WNL.0000000000009924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455356PMC
August 2020

Global Assessment of Mendelian Stroke Genetic Prevalence in 101 635 Individuals From 7 Ethnic Groups.

Stroke 2020 04 28;51(4):1290-1293. Epub 2020 Feb 28.

From the Population Health Research Institute, the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada (N.G., M.C., R.L., P.M.-S., G.P.).

Background and Purpose- Mendelian stroke confers a high lifetime risk for mutation carriers; however, ethnicity-specific prevalence estimates have been difficult to establish. Methods- Eighteen genes responsible for Mendelian stroke were investigated using the Genome Aggregation Database. Genome Aggregation Database participants belonged to 1 of 7 populations: African/African-American, Latino/Admixed American, Ashkenazi Jewish, East Asian, Finnish European, non-Finnish European, and South Asian. Rare nonsynonymous variants from 101 635 participants free of neurological disease were examined for each ethnicity. Mutations were categorized according to 3 nested classes: pathogenic clinical variants, likely damaging variants based on in silico prediction, and all nonsynonymous variants. Results- , , , , , , , , , , , and harbored pathogenic clinical variants in Genome Aggregation Database. Across all 18 genes, total nonsynonymous carrier frequency was found to be high in 5 ethnicities (African/African-American, Latino/Admixed American, East Asian, non-Finnish European, and South Asian; 28.5%-37.5%) while lower total frequencies were estimated for in silico-predicted likely damaging variants (14.9%-19.7%) and pathogenic clinical variants (0.7%-2.8%). Overall, East Asian exhibited the highest total pathogenic clinical mutation carrier frequency (2.8%). pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic variants, causal for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were most frequent among East Asian (1.1%) and South Asian (1.2%). East Asian also demonstrated the highest carrier rate for (0.8%). Finnish European exhibited the greatest frequency (0.2%), while pathogenic variants were most prevalent in African/African-American (0.3%). Conclusions- Especially, among pathogenic clinical variants, Mendelian stroke genetic prevalence differed significantly between populations. These prevalence estimates may serve as guides for screening and risk profiling in patients worldwide, particularly for understudied non-European populations.
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http://dx.doi.org/10.1161/STROKEAHA.119.028840DOI Listing
April 2020

Case report: immune-mediated cerebellar ataxia secondary to anti-PD-L1 treatment for lung cancer.

Int J Neurosci 2019 Dec 28;129(12):1223-1225. Epub 2019 Aug 28.

Department of Medical Oncology, Beatson West of Scotland Cancer Centre , Glasgow , Scotland.

A 66-year-old gentleman with metastatic non-small-cell lung cancer developed a wide-based gait following treatment on a clinical trial with cytotoxic chemotherapy and an anti-PD-L1 drug. He had no other significant past medical history of note. Brain imaging, blood tests and lumbar puncture did not reveal a structural, biochemical, paraneoplastic or infective cause. The main differential diagnoses were immune-mediated toxicity or a paraneoplastic syndrome. He was started on prednisolone on the suspicion that his symptoms represented an immune-mediated toxicity. His condition improved following this and his immunotherapy treatment was discontinued. Upon steroid withdrawal, his symptoms recurred and responded to further prednisolone. Immune-mediated toxicities can affect any part of the nervous system and should form part of the differential diagnosis for new neurological symptoms in a patient receiving immunotherapy. Corticosteroids should be the first-line treatment of immune-mediated toxicities. Immunotherapy should be permanently discontinued following severe toxicities.
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http://dx.doi.org/10.1080/00207454.2019.1655013DOI Listing
December 2019

Epilepsia partialis continua complicated by disseminated tuberculosis and hemophagocytic lymphohistiocytosis: a case report.

J Med Case Rep 2019 Jun 24;13(1):191. Epub 2019 Jun 24.

Forth Valley Royal Hospital, Larbert, and Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.

Background: We describe a patient copresenting with epilepsia partialis continua, tuberculosis, and hemophagocytic lymphohistiocytosis. To our knowledge, this is the first documented case of this triad.

Case Presentation: A 54-year-old black South African woman presented to a hospital in Scotland with an acute history of right-sided facial twitching, breathlessness, and several months of episodic night sweats. Clinical examination revealed pyrexia and continuous, stereotyped, right-sided facial contractions. These worsened with speech and continued through sleep. A clinical diagnosis of epilepsia partialis continua was made, and we provide a video of her seizures. Computed tomographic imaging of the chest and serous fluid analyses were consistent with a diagnosis of disseminated Mycobacterium tuberculosis. An additional diagnosis of hemophagocytic lymphohistiocytosis was made following the identification of pancytopenia and hyperferritinemia in peripheral blood, with hemophagocytosis evident in bone marrow investigation. We provide images of her hematopathology. The patient was extremely unwell and was hospitalized for 6 months, including two admissions to the intensive care unit for ventilatory support. She was treated successfully with high doses of antiepileptic drugs (benzodiazepines, levetiracetam, and phenytoin) and 12 months of oral antituberculosis therapy, and she underwent chemotherapy with 8 weeks of etoposide and dexamethasone for hemophagocytic lymphohistiocytosis, followed by 12 months of cyclosporine and prednisolone.

Conclusions: This combination of pathologies is unusual, and this case report helps educate clinicians on how such a patient may present and be managed. A lack of evidence surrounding the coexpression of this triad may represent absolute rarity, underdiagnosis, or incomplete case ascertainment due to early death caused by untreated tuberculosis or hemophagocytic lymphohistiocytosis. Further research is needed.
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http://dx.doi.org/10.1186/s13256-019-2092-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589876PMC
June 2019

Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Authors:
Rainer Malik Ganesh Chauhan Matthew Traylor Muralidharan Sargurupremraj Yukinori Okada Aniket Mishra Loes Rutten-Jacobs Anne-Katrin Giese Sander W van der Laan Solveig Gretarsdottir Christopher D Anderson Michael Chong Hieab H H Adams Tetsuro Ago Peter Almgren Philippe Amouyel Hakan Ay Traci M Bartz Oscar R Benavente Steve Bevan Giorgio B Boncoraglio Robert D Brown Adam S Butterworth Caty Carrera Cara L Carty Daniel I Chasman Wei-Min Chen John W Cole Adolfo Correa Ioana Cotlarciuc Carlos Cruchaga John Danesh Paul I W de Bakker Anita L DeStefano Marcel den Hoed Qing Duan Stefan T Engelter Guido J Falcone Rebecca F Gottesman Raji P Grewal Vilmundur Gudnason Stefan Gustafsson Jeffrey Haessler Tamara B Harris Ahamad Hassan Aki S Havulinna Susan R Heckbert Elizabeth G Holliday George Howard Fang-Chi Hsu Hyacinth I Hyacinth M Arfan Ikram Erik Ingelsson Marguerite R Irvin Xueqiu Jian Jordi Jiménez-Conde Julie A Johnson J Wouter Jukema Masahiro Kanai Keith L Keene Brett M Kissela Dawn O Kleindorfer Charles Kooperberg Michiaki Kubo Leslie A Lange Carl D Langefeld Claudia Langenberg Lenore J Launer Jin-Moo Lee Robin Lemmens Didier Leys Cathryn M Lewis Wei-Yu Lin Arne G Lindgren Erik Lorentzen Patrik K Magnusson Jane Maguire Ani Manichaikul Patrick F McArdle James F Meschia Braxton D Mitchell Thomas H Mosley Michael A Nalls Toshiharu Ninomiya Martin J O'Donnell Bruce M Psaty Sara L Pulit Kristiina Rannikmäe Alexander P Reiner Kathryn M Rexrode Kenneth Rice Stephen S Rich Paul M Ridker Natalia S Rost Peter M Rothwell Jerome I Rotter Tatjana Rundek Ralph L Sacco Saori Sakaue Michele M Sale Veikko Salomaa Bishwa R Sapkota Reinhold Schmidt Carsten O Schmidt Ulf Schminke Pankaj Sharma Agnieszka Slowik Cathie L M Sudlow Christian Tanislav Turgut Tatlisumak Kent D Taylor Vincent N S Thijs Gudmar Thorleifsson Unnur Thorsteinsdottir Steffen Tiedt Stella Trompet Christophe Tzourio Cornelia M van Duijn Matthew Walters Nicholas J Wareham Sylvia Wassertheil-Smoller James G Wilson Kerri L Wiggins Qiong Yang Salim Yusuf Joshua C Bis Tomi Pastinen Arno Ruusalepp Eric E Schadt Simon Koplev Johan L M Björkegren Veronica Codoni Mete Civelek Nicholas L Smith David A Trégouët Ingrid E Christophersen Carolina Roselli Steven A Lubitz Patrick T Ellinor E Shyong Tai Jaspal S Kooner Norihiro Kato Jiang He Pim van der Harst Paul Elliott John C Chambers Fumihiko Takeuchi Andrew D Johnson Dharambir K Sanghera Olle Melander Christina Jern Daniel Strbian Israel Fernandez-Cadenas W T Longstreth Arndt Rolfs Jun Hata Daniel Woo Jonathan Rosand Guillaume Pare Jemma C Hopewell Danish Saleheen Kari Stefansson Bradford B Worrall Steven J Kittner Sudha Seshadri Myriam Fornage Hugh S Markus Joanna M M Howson Yoichiro Kamatani Stephanie Debette Martin Dichgans

Nat Genet 2019 Jul;51(7):1192-1193

Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 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/s41588-019-0449-0DOI Listing
July 2019

Identifying dementia outcomes in UK Biobank: a validation study of primary care, hospital admissions and mortality data.

Eur J Epidemiol 2019 Jun 26;34(6):557-565. Epub 2019 Feb 26.

Centre for Medical Informatics, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Prospective, population-based studies that recruit participants in mid-life are valuable resources for dementia research. Follow-up in these studies is often through linkage to routinely-collected healthcare datasets. We investigated the accuracy of these datasets for dementia case ascertainment in a validation study using data from UK Biobank-an open access, population-based study of > 500,000 adults aged 40-69 years at recruitment in 2006-2010. From 17,198 UK Biobank participants recruited in Edinburgh, we identified those with ≥ 1 dementia code in their linked primary care, hospital admissions or mortality data and compared their coded diagnoses to clinical expert adjudication of their full-text medical record. We calculated the positive predictive value (PPV, the proportion of cases identified that were true positives) for all-cause dementia, Alzheimer's disease and vascular dementia for each dataset alone and in combination, and explored algorithmic code combinations to improve PPV. Among 120 participants, PPVs for all-cause dementia were 86.8%, 87.3% and 80.0% for primary care, hospital admissions and mortality data respectively and 82.5% across all datasets. We identified three algorithms that balanced a high PPV with reasonable case ascertainment. For Alzheimer's disease, PPVs were 74.1% for primary care, 68.2% for hospital admissions, 50.0% for mortality data and 71.4% in combination. PPV for vascular dementia was 43.8% across all sources. UK routinely-collected healthcare data can be used to identify all-cause dementia in prospective studies. PPVs for Alzheimer's disease and vascular dementia are lower. Further research is required to explore the geographic generalisability of these findings.
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http://dx.doi.org/10.1007/s10654-019-00499-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497624PMC
June 2019

Genome-wide association meta-analysis of functional outcome after ischemic stroke.

Neurology 2019 03 22;92(12):e1271-e1283. Epub 2019 Feb 22.

Objective: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.

Methods: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was < 5 × 10.

Results: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, = 5.3 × 10). This intronic variant (rs1842681) in the gene is a previously reported trans-expression quantitative trait locus for , which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome ( < 10), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., , , and ).

Conclusions: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
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http://dx.doi.org/10.1212/WNL.0000000000007138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511098PMC
March 2019

Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity: A Meta-analysis.

JAMA Neurol 2019 04;76(4):480-491

Center for Genomic Medicine, Massachusetts General Hospital, Boston.

Importance: Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.

Objective: To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.

Design, Setting, And Participants: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.

Main Outcomes And Measures: Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.

Results: In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.

Conclusions And Relevance: APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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http://dx.doi.org/10.1001/jamaneurol.2018.4519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459133PMC
April 2019

Identifying Parkinson's disease and parkinsonism cases using routinely collected healthcare data: A systematic review.

PLoS One 2019 31;14(1):e0198736. Epub 2019 Jan 31.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Background: Population-based, prospective studies can provide important insights into Parkinson's disease (PD) and other parkinsonian disorders. Participant follow-up in such studies is often achieved through linkage to routinely collected healthcare datasets. We systematically reviewed the published literature on the accuracy of these datasets for this purpose.

Methods: We searched four electronic databases for published studies that compared PD and parkinsonism cases identified using routinely collected data to a reference standard. We extracted study characteristics and two accuracy measures: positive predictive value (PPV) and/or sensitivity.

Results: We identified 18 articles, resulting in 27 measures of PPV and 14 of sensitivity. For PD, PPV ranged from 56-90% in hospital datasets, 53-87% in prescription datasets, 81-90% in primary care datasets and was 67% in mortality datasets. Combining diagnostic and medication codes increased PPV. For parkinsonism, PPV ranged from 36-88% in hospital datasets, 40-74% in prescription datasets, and was 94% in mortality datasets. Sensitivity ranged from 15-73% in single datasets for PD and 43-63% in single datasets for parkinsonism.

Conclusions: In many settings, routinely collected datasets generate good PPVs and reasonable sensitivities for identifying PD and parkinsonism cases. However, given the wide range of identified accuracy estimates, we recommend cohorts conduct their own context-specific validation studies if existing evidence is lacking. Further research is warranted to investigate primary care and medication datasets, and to develop algorithms that balance a high PPV with acceptable sensitivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198736PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354966PMC
September 2019

Genetically Determined Levels of Circulating Cytokines and Risk of Stroke.

Circulation 2019 01;139(2):256-268

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

Background: Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study.

Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance-weighted meta-analysis, weighted-median analysis, Mendelian randomization-Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data.

Results: Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02-1.09; P=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02-1.10; P=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09-1.30; P=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06-1.23; P=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99-1.17; P=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97-1.18; P=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00-1.08; P=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01-1.09; P=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls.

Conclusions: Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477819PMC
January 2019

PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome.

Circ Res 2019 01;124(1):114-120

From the Department of Neurology, Neurovascular Research Group, Hospital del Mar Medical Research Institute, Universitat Autònoma de Barcelona/DCEXS-Universitat Pompeu Fabra (M.M.-C., C.S.-T., E.G.-S., A.R.-C., A.O., E.C.-G., R.M.V.-H., J.R., J.J.-C.).

Rationale: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.

Objective: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.

Methods And Results: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10).

Conclusions: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501820PMC
January 2019

Genome-wide meta-analysis identifies 3 novel loci associated with stroke.

Ann Neurol 2018 12 30;84(6):934-939. Epub 2018 Nov 30.

Institute for Stroke and Dementia Research, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

We conducted a European-only and transancestral genome-wide association meta-analysis in 72,147 stroke patients and 823,869 controls using data from UK Biobank (UKB) and the MEGASTROKE consortium. We identified an exonic polymorphism in NOS3 (rs1799983, p.Glu298Asp; p = 2.2E-8, odds ratio [OR] = 1.05, 95% confidence interval [CI] = 1.04-1.07) and variants in an intron of COL4A1 (rs9521634; p = 3.8E-8, OR = 1.04, 95% CI = 1.03-1.06) and near DYRK1A (rs720470; p = 6.1E-9, OR = 1.05, 95% CI = 1.03-1.07) at genome-wide significance for stroke. Effect sizes of known stroke loci were highly correlated between UKB and MEGASTROKE. Using Mendelian randomization, we further show that genetic variation in the nitric oxide synthase-nitric oxide pathway in part affects stroke risk via variation in blood pressure. Ann Neurol 2018;84:934-939.
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http://dx.doi.org/10.1002/ana.25369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644297PMC
December 2018

Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306 473 UK Biobank participants.

BMJ 2018 Oct 24;363:k4168. Epub 2018 Oct 24.

Department of Clinical Neurosciences, Stroke Research Group, University of Cambridge, UK.

Objective: To evaluate the associations of a polygenic risk score and healthy lifestyle with incident stroke.

Design: Prospective population based cohort study.

Setting: UK Biobank Study, UK.

Participants: 306 473 men and women, aged 40-73 years, recruited between 2006 and 2010.

Main Outcome Measure: Hazard ratios for a first stroke, estimated using Cox regression. A polygenic risk score of 90 single nucleotide polymorphisms previously associated with stroke was constructed at P<1×10 to test for an association with incident stroke. Adherence to a healthy lifestyle was determined on the basis of four factors: non-smoker, healthy diet, body mass index <30 kg/m, and regular physical exercise.

Results: During a median follow-up of 7.1 years (2 138 443 person years), 2077 incident strokes (1541 ischaemic stroke, 287 intracerebral haemorrhage, and 249 subarachnoid haemorrhage) were ascertained. The risk of incident stroke was 35% higher among those at high genetic risk (top third of polygenic score) compared with those at low genetic risk (bottom third): hazard ratio 1.35 (95% confidence interval 1.21 to 1.50), P=3.9×10. Unfavourable lifestyle (0 or 1 healthy lifestyle factors) was associated with a 66% increased risk of stroke compared with a favourable lifestyle (3 or 4 healthy lifestyle factors): 1.66 (1.45 to 1.89), P=1.19×10. The association with lifestyle was independent of genetic risk stratums.

Conclusion: In this cohort study, genetic and lifestyle factors were independently associated with incident stroke. These results emphasise the benefit of entire populations adhering to a healthy lifestyle, independent of genetic risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199557PMC
http://dx.doi.org/10.1136/bmj.k4168DOI Listing
October 2018

Identifying dementia cases with routinely collected health data: A systematic review.

Alzheimers Dement 2018 08 3;14(8):1038-1051. Epub 2018 Apr 3.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Scotland; Usher Institute of Population Health Sciences and Informatics, Nine Bioquarter, Edinburgh, Scotland; UK Biobank, Coordinating Centre, Stockport, UK.

Introduction: Prospective, population-based studies can be rich resources for dementia research. Follow-up in many such studies is through linkage to routinely collected, coded health-care data sets. We evaluated the accuracy of these data sets for dementia case identification.

Methods: We systematically reviewed the literature for studies comparing dementia coding in routinely collected data sets to any expert-led reference standard. We recorded study characteristics and two accuracy measures-positive predictive value (PPV) and sensitivity.

Results: We identified 27 eligible studies with 25 estimating PPV and eight estimating sensitivity. Study settings and methods varied widely. For all-cause dementia, PPVs ranged from 33%-100%, but 16/27 were >75%. Sensitivities ranged from 21% to 86%. PPVs for Alzheimer's disease (range 57%-100%) were generally higher than those for vascular dementia (range 19%-91%).

Discussion: Linkage to routine health-care data can achieve a high PPV and reasonable sensitivity in certain settings. Given the heterogeneity in accuracy estimates, cohorts should ideally conduct their own setting-specific validation.
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http://dx.doi.org/10.1016/j.jalz.2018.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105076PMC
August 2018

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

Authors:
Rainer Malik Ganesh Chauhan Matthew Traylor Muralidharan Sargurupremraj Yukinori Okada Aniket Mishra Loes Rutten-Jacobs Anne-Katrin Giese Sander W van der Laan Solveig Gretarsdottir Christopher D Anderson Michael Chong Hieab H H Adams Tetsuro Ago Peter Almgren Philippe Amouyel Hakan Ay Traci M Bartz Oscar R Benavente Steve Bevan Giorgio B Boncoraglio Robert D Brown Adam S Butterworth Caty Carrera Cara L Carty Daniel I Chasman Wei-Min Chen John W Cole Adolfo Correa Ioana Cotlarciuc Carlos Cruchaga John Danesh Paul I W de Bakker Anita L DeStefano Marcel den Hoed Qing Duan Stefan T Engelter Guido J Falcone Rebecca F Gottesman Raji P Grewal Vilmundur Gudnason Stefan Gustafsson Jeffrey Haessler Tamara B Harris Ahamad Hassan Aki S Havulinna Susan R Heckbert Elizabeth G Holliday George Howard Fang-Chi Hsu Hyacinth I Hyacinth M Arfan Ikram Erik Ingelsson Marguerite R Irvin Xueqiu Jian Jordi Jiménez-Conde Julie A Johnson J Wouter Jukema Masahiro Kanai Keith L Keene Brett M Kissela Dawn O Kleindorfer Charles Kooperberg Michiaki Kubo Leslie A Lange Carl D Langefeld Claudia Langenberg Lenore J Launer Jin-Moo Lee Robin Lemmens Didier Leys Cathryn M Lewis Wei-Yu Lin Arne G Lindgren Erik Lorentzen Patrik K Magnusson Jane Maguire Ani Manichaikul Patrick F McArdle James F Meschia Braxton D Mitchell Thomas H Mosley Michael A Nalls Toshiharu Ninomiya Martin J O'Donnell Bruce M Psaty Sara L Pulit Kristiina Rannikmäe Alexander P Reiner Kathryn M Rexrode Kenneth Rice Stephen S Rich Paul M Ridker Natalia S Rost Peter M Rothwell Jerome I Rotter Tatjana Rundek Ralph L Sacco Saori Sakaue Michele M Sale Veikko Salomaa Bishwa R Sapkota Reinhold Schmidt Carsten O Schmidt Ulf Schminke Pankaj Sharma Agnieszka Slowik Cathie L M Sudlow Christian Tanislav Turgut Tatlisumak Kent D Taylor Vincent N S Thijs Gudmar Thorleifsson Unnur Thorsteinsdottir Steffen Tiedt Stella Trompet Christophe Tzourio Cornelia M van Duijn Matthew Walters Nicholas J Wareham Sylvia Wassertheil-Smoller James G Wilson Kerri L Wiggins Qiong Yang Salim Yusuf Joshua C Bis Tomi Pastinen Arno Ruusalepp Eric E Schadt Simon Koplev Johan L M Björkegren Veronica Codoni Mete Civelek Nicholas L Smith David A Trégouët Ingrid E Christophersen Carolina Roselli Steven A Lubitz Patrick T Ellinor E Shyong Tai Jaspal S Kooner Norihiro Kato Jiang He Pim van der Harst Paul Elliott John C Chambers Fumihiko Takeuchi Andrew D Johnson Dharambir K Sanghera Olle Melander Christina Jern Daniel Strbian Israel Fernandez-Cadenas W T Longstreth Arndt Rolfs Jun Hata Daniel Woo Jonathan Rosand Guillaume Pare Jemma C Hopewell Danish Saleheen Kari Stefansson Bradford B Worrall Steven J Kittner Sudha Seshadri Myriam Fornage Hugh S Markus Joanna M M Howson Yoichiro Kamatani Stephanie Debette Martin Dichgans

Nat Genet 2018 04 12;50(4):524-537. Epub 2018 Mar 12.

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

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.
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http://dx.doi.org/10.1038/s41588-018-0058-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968830PMC
April 2018

Rare variants of the 3'-5' DNA exonuclease in early onset small vessel stroke.

Wellcome Open Res 2017 2;2:106. Epub 2017 Nov 2.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.

Monoallelic and biallelic mutations in the exonuclease cause monogenic small vessel diseases (SVD). Given recent evidence for genetic and pathophysiological overlap between monogenic and polygenic forms of SVD, evaluation of in small vessel stroke is warranted. We sequenced the gene in an exploratory cohort of patients with lacunar stroke (Edinburgh Stroke Study, n=290 lacunar stroke cases). We subsequently performed a fully blinded case-control study of early onset MRI-confirmed small vessel stroke within the UK Young Lacunar Stroke Resource (990 cases, 939 controls). No patients with canonical disease-causing mutations of were identified in cases or controls. Analysis of an exploratory cohort identified a potential association between rare variants of and patients with lacunar stroke. However, subsequent controlled and blinded evaluation of in a larger and MRI-confirmed patient cohort, the UK Young Lacunar Stroke Resource, identified heterozygous rare variants in 2.1% of cases and 2.3% of controls. No association was observed with stroke risk (odds ratio = 0.90; 95% confidence interval, 0.49-1.65 p=0.74). Similarly no association was seen with rare variants with predicted deleterious effects on enzyme function (odds ratio = 1.05; 95% confidence interval, 0.43-2.61 p=0.91). No patients with early-onset lacunar stroke had genetic evidence of a -associated monogenic microangiopathy. These results show no evidence of association between rare variants of and early onset lacunar stroke. This includes rare variants that significantly affect protein and enzyme function. Routine sequencing of the gene in patients with early onset lacunar stroke is therefore unlikely to be of diagnostic utility, in the absence of syndromic features or family history.
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http://dx.doi.org/10.12688/wellcomeopenres.12631.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717473PMC
November 2017

is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.

Neurology 2017 Oct 27;89(17):1829-1839. Epub 2017 Sep 27.

From the Centre for Clinical Brain Sciences (K.R., C.L.M.S.), College of Medicine and Veterinary Medicine (V.S., H.M.), and Institute for Genetics and Molecular Medicine (C.L.M.S.), University of Edinburgh, UK; Institute for Stroke and Dementia Research (R.M., M.D.), Klinikum der Universität München, Munich, Germany; Center for Human Genetic Research (C.D.A., F.R., J.R.) and J. Philip Kistler Stroke Research Center (C.D.A., F.R., N.S.R., J.R.) and Division of Neurocritical Care and Emergency Neurology (C.D.A., F.R., J.R.), Department of Neurology, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics (C.D.A., F.R., J.R.), Broad Institute, Cambridge, MA; Population Health Research Institute (M.C., M.O., G.P.), McMaster University, Hamilton Health Sciences Centre, Ontario, Canada; Department of Medicine (T.D., B.D.M.), University of Maryland School of Medicine, Baltimore; Division of Neurocritical Care and Emergency Neurology (G.J.F.), Department of Neurology, Yale University School of Medicine, New Haven, CT; Stroke Pharmacogenomics and Genetics (I.F.-C.), Fundació Docència i Recerca Mutua Terrassa, Mutua de Terrassa Hospital; Neurovascular Research Unit (J.J.-C.), Department of Neurology, and Program in Inflammation and Cardiovascular Disorders (J.J.-C.), Institut Municipal d'Investigacio´Medica-Hospital del Mar, Universitat Autonoma de Barcelona, Spain; Department of Clinical Sciences Lund (A.L.), Neurology, Lund University; Department of Neurology and Rehabilitation Medicine (A.L., M.S.), Neurology, Skåne University Hospital, Lund, Sweden; Neurovascular Research Laboratory and Neurovascular Unit (J.M.), Institut de Recerca, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; HRB Clinical Research Facility (M.O.), NUI Galway, and University Hospital Galway, Ireland; Department of Neurology (A.S.), Jagiellonian University Medical College, Krakow, Poland; Cardiovascular Epidemiology Research Group (M.S.), Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Clinical Neurosciences (M.T., H.S.M.), University of Cambridge, UK; Department of Neurology (S.L.P.), Brain Centre Rudolf Magnus, University Medical Center Utrecht, the Netherlands; Boston University Schools of Medicine and Public Health (S.S.); Framingham Heart Study (S.S.), Framingham, MA; Departments of Neurology and Public Health Sciences (B.B.W.), University of Virginia, Charlottesville; Department of Neurology (D.W.), University of Cincinnati College of Medicine, OH; Geriatrics Research and Education Clinical Center (B.D.M.), Baltimore Veterans Administration Medical Center, MD; and Munich Cluster for Systems Neurology (SyNergy) (M.D.), Germany.

Objective: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.

Methods: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (, , , , , and ) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.

Results: A locus in was associated (significance threshold < 3.5 × 10) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11-1.24, = 6.62 × 10) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13-1.44, = 5.76 × 10). A SNP in was associated (significance threshold < 5.5 × 10) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10-1.37, = 1.90 × 10) and less robustly with deep ICH. There was no clear evidence for association of common variants in either or with non-SVD strokes or in any of the other genes with any stroke phenotype.

Conclusions: These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.
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http://dx.doi.org/10.1212/WNL.0000000000004560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664302PMC
October 2017

GISCOME - Genetics of Ischaemic Stroke Functional Outcome network: A protocol for an international multicentre genetic association study.

Eur Stroke J 2017 Sep 19;2(3):229-237. Epub 2017 Apr 19.

Department of Clinical Sciences Lund, Neurology, Lund University, Sweden.

Introduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome.

Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data.

Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60-190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses.

Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.
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http://dx.doi.org/10.1177/2396987317704547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454830PMC
September 2017

Common coding variant in increases the risk for large artery stroke.

Proc Natl Acad Sci U S A 2017 04 6;114(14):3613-3618. Epub 2017 Mar 6.

Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich 81377, Germany;

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 () encoding alpha-1 antitrypsin [AAT; p.V213A; = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 () as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.
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http://dx.doi.org/10.1073/pnas.1616301114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389268PMC
April 2017

Accuracy of routinely-collected healthcare data for identifying motor neurone disease cases: A systematic review.

PLoS One 2017 28;12(2):e0172639. Epub 2017 Feb 28.

Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom.

Background: Motor neurone disease (MND) is a rare neurodegenerative condition, with poorly understood aetiology. Large, population-based, prospective cohorts will enable powerful studies of the determinants of MND, provided identification of disease cases is sufficiently accurate. Follow-up in many such studies relies on linkage to routinely-collected health datasets. We systematically evaluated the accuracy of such datasets in identifying MND cases.

Methods: We performed an electronic search of MEDLINE, EMBASE, Cochrane Library and Web of Science for studies published between 01/01/1990-16/11/2015 that compared MND cases identified in routinely-collected, coded datasets to a reference standard. We recorded study characteristics and two key measures of diagnostic accuracy-positive predictive value (PPV) and sensitivity. We conducted descriptive analyses and quality assessments of included studies.

Results: Thirteen eligible studies provided 13 estimates of PPV and five estimates of sensitivity. Twelve studies assessed hospital and/or death certificate-derived datasets; one evaluated a primary care dataset. All studies were from high income countries (UK, Europe, USA, Hong Kong). Study methods varied widely, but quality was generally good. PPV estimates ranged from 55-92% and sensitivities from 75-93%. The single (UK-based) study of primary care data reported a PPV of 85%.

Conclusions: Diagnostic accuracy of routinely-collected health datasets is likely to be sufficient for identifying cases of MND in large-scale prospective epidemiological studies in high income country settings. Primary care datasets, particularly from countries with a widely-accessible national healthcare system, are potentially valuable data sources warranting further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172639PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330471PMC
August 2017

Genetic variants in CETP increase risk of intracerebral hemorrhage.

Ann Neurol 2016 11 19;80(5):730-740. Epub 2016 Oct 19.

Center for Human Genetic Research, Massachusetts General Hospital (MGH), Boston, MA.

Objective: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.

Methods: We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.

Results: Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR] = 1.25, standard error [SE] = 0.06, p = 6.0 × 10 ) with no heterogeneity across studies (I  = 0%). This association was replicated in patients of European ancestry (p = 0.03). A genetic score of CETP variants found to increase HDL-C by ∼2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR = 1.86, SE = 0.13, p = 1.39 × 10 ).

Interpretation: Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
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http://dx.doi.org/10.1002/ana.24780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5115931PMC
November 2016

Reliability of intracerebral hemorrhage classification systems: A systematic review.

Int J Stroke 2016 08 18;11(6):626-36. Epub 2016 Apr 18.

Centre for Clinical Brain Sciences, University of Edinburgh, UK Institute for Genetics and Molecular Medicine, University of Edinburgh, UK UK Biobank, UK

Background: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems.

Methods: We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies' characteristics, reporting quality and potential for bias; summarized reliability with kappa value forest plots; and performed meta-analyses of the proportion of cases classified into each subtype.

Summary Of Review: We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78-0.97 [six studies, 518 cases], mechanistic 0.89-0.93 [three studies, 510 cases]; intra-rater kappas: anatomical 0.80-1 [three studies, 137 cases], mechanistic 0.92-0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative.

Conclusions: Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines.
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http://dx.doi.org/10.1177/1747493016641962DOI Listing
August 2016

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.

Neurology 2015 May 1;84(21):2132-45. Epub 2015 May 1.

Author affiliations are provided at the end of the article.

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO).

Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.
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http://dx.doi.org/10.1212/WNL.0000000000001606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451048PMC
May 2015

Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease.

Neurology 2015 Mar 4;84(9):918-26. Epub 2015 Feb 4.

Authors' affiliations are listed at the end of the article.

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.

Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).

Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.

Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
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http://dx.doi.org/10.1212/WNL.0000000000001309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351667PMC
March 2015

Estonia.

Pract Neurol 2015 Apr 8;15(2):127-30. Epub 2015 Jan 8.

Department of Neurology, Tartu University Hospital, Tartu, Estonia Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.

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http://dx.doi.org/10.1136/practneurol-2014-001058DOI Listing
April 2015