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BackgroundPrevious studies have suggested that some medications may influence dementia risk. We conducted a hypothesis-generating medication-wide association study to investigate systematically the association between all prescription medications and incident dementia.MethodsWe used a population-based cohort within the Secure Anonymised Information Linkage (SAIL) databank, comprising routinely-collected primary care, hospital admissions and mortality data from Wales, UK. We included all participants born after 1910 and registered with a SAIL general practice at ≤60 years old. Follow-up was from each participant’s 60th birthday to the earliest of dementia diagnosis, deregistration from a SAIL general practice, death or the end of 2018. We considered participants exposed to a medication if they received ≥1 prescription for any of 744 medications before or during follow-up. We adjusted for sex, smoking and socioeconomic status. The outcome was any all-cause dementia code in primary care, hospital or mortality data during follow-up. We used Cox regression to calculate hazard ratios and Bonferroni-corrected p values.ResultsOf 551 344 participants, 16 998 (3%) developed dementia (median follow-up was 17 years for people who developed dementia, 10 years for those without dementia). Of 744 medications, 221 (30%) were associated with dementia. Of these, 217 (98%) were associated with increased dementia incidence, many clustering around certain indications. Four medications (all vaccines) were associated with a lower dementia incidence.ConclusionsAlmost a third of medications were associated with dementia. The clustering of many drugs around certain indications may provide insights into early manifestations of dementia. We encourage further investigation of hypotheses generated by these results.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

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— ABCC6 , KRIT1 , CECR1 , COL3A1 , COL4A1 , COL4A2 , COLGALT1 , GLA , HTRA1 , NOTCH3 , RNF213 , and TREX1 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%). ABCC6 pathogenic clinical variants were most prevalent among East Asian (0.8%). Pathogenic NOTCH3 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 RNF213 (0.8%). Finnish European exhibited the greatest HTRA1 frequency (0.2%), while COL4A1 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.

Based on previous case reports and disease-based cohorts, a minority of patients with cerebral small vessel disease (cSVD) have a monogenic cause, with many also manifesting extra-cerebral phenotypes. We investigated the frequency, penetrance, and phenotype associations of rare variants in cSVD genes in UK Biobank (UKB), a large population-based study.We used a systematic review of previous literature and ClinVar to identify putative pathogenic rare variants in CTSA, TREX1, HTRA1, COL4A1/2. We mapped phenotypes previously attributed to these variants (phenotypes-of-interest) to disease coding systems used in UKB’s linked health data from UK hospital admissions, death records and primary care. Among 199,313 exome-sequenced UKB participants, we assessed: the proportion of participants carrying ≥1 variant(s); phenotype-of-interest penetrance; and the association between variant carrier status and phenotypes-of-interest using a binary (any phenotype present/absent) and phenotype burden (linear score of the number of phenotypes a participant possessed) approach.Among UKB participants, 0.5% had ≥1 variant(s) in studied genes. Using hospital admission and death records, 4-20% of variant carriers per gene had an associated phenotype. This increased to 7-55% when including primary care records. Only COL4A1 variant carrier-status was significantly associated with having ≥1 phenotype-of-interest and a higher phenotype score (OR=1.29, p=0.006).While putative pathogenic rare variants in monogenic cSVD genes occur in 1:200 people in the UKB population, only around half of variant carriers have a relevant disease phenotype recorded in their linked health data. We could not replicate most previously reported gene-phenotype associations, suggesting lower penetrance rates, overestimated pathogenicity and/or limited statistical power.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

BackgroundStroke in UK Biobank (UKB) is ascertained via linkages to coded administrative datasets and self-report. We studied the accuracy of these codes using genetic validation.MethodsWe compiled stroke-specific and broad cerebrovascular disease (CVD) code lists (Read V2/V3, ICD-9/-10) for medical settings (hospital, death record, primary care) and self-report. Among 408,210 UKB participants we identified all with a relevant code, creating 12 stroke definitions based on the code type and source. We performed genome-wide association studies (GWASs) for each definition, comparing summary results against the largest published stroke GWAS (MEGASTROKE), assessing genetic correlations, and replicating 32 stroke-associated loci.ResultsStroke case numbers identified varied widely from 3,976 (primary care stroke-specific codes) to 19,449 (all codes, all sources). All 12 UKB stroke definitions were significantly correlated with the MEGASTROKE summary GWAS results (rg 0.81-1) and each other (rg 0.4-1). However, Bonferroni-corrected confidence intervals were wide, suggesting limited precision of some results. Six previously reported stroke-associated loci were replicated using ≥1 UKB stroke definitions.ConclusionsStroke case numbers in UKB depend on the code source and type used, with a 5-fold difference in the maximum case-sample size. All stroke definitions are significantly genetically correlated with the largest stroke GWAS to date.

Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author.

ObjectiveIn 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.MethodsIn 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.ResultsOf 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.ConclusionsStroke 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.

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. However routinely collected coded data cannot always provide sufficient accuracy or granularity (i.e. sub-phenotypes) for research studies. For example, while ischemic stroke codes appear accurate, the precision for hemorrhagic stroke codes (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH]) may be as poor as Methods: From a sub-population of 17,249 UKB participants, we ascertained those with an incident stroke code and ≥1 clinical brain scan report. We used automated methods (a combination of natural language processing and clinical knowledge inference) on brain scan reports to assign a stroke subtype (ischemic vs ICH vs SAH) for each participant and assessed performance by precision (positive predictive value) and recall (sensitivity) at both entity and patient levels. Results: Of 225 participants with an incident stroke code, 207 had a relevant brain scan report. Entity level precision and recall ranged from 78% to 100%. Automated methods showed precision (positive predictive value) and recall (sensitivity) at patient level that were very good for ICH (both 89%), good for SAH (both 82%), but, as expected, lower for ischemic stroke (73%, and 64%, respectively), suggesting coded data remains the preferred method for identifying the latter stroke subtype (Table 1). Discussion: Future research should validate these findings in another dataset. Conclusion: Our novel automated method applied to radiology reports provides a feasible, scalable and accurate solution to improve disease subtyping when used in conjunction with administrative coded health data.

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.

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.

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 COL4A1/2 , TREX1 , HTRA1 , ADA2 , and CTSA 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 COL4A1 (350 individuals), 32 TREX1 (115 individuals), 43 HTRA1 (38 homozygous/61 heterozygous individuals), 16 COL4A2 (37 individuals), 119 ADA2 (209 individuals), and 3 CTSA (14 individuals) publications. The majority of individuals originated from Europe/North America, except for HTRA1 , where most were from Asia. Age varied widely, ADA2 individuals being youngest and heterozygous HTRA1/CTSA 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% COL4A2 , 43% HTRA1 heterozygotes, 47% COL4A1 , 57% TREX1 , 91% ADA2 , 94% HTRA1 homozygotes, and 100% CTSA 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.

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.

Background Recent studies have reported conflicting associations between drug prescriptions and incident dementia. Any association between drug and dementia could be due to the drugs directly causing or preventing dementia; the drugs being associated with a risk factor for dementia; or the drugs being prescribed as a consequence of prodromal dementia. Based on methodology developed for genome-wide association studies, we systematically analyzed the effect of 733 drugs on incident dementia in a population-wide linkage study and clinically reviewed the associations. Methods Using linked, routinely-collected electronic health records from hospital admissions, mortality records and primary care consultations, we followed-up 574,237 Welsh residents from their 60th birthday onwards to classify exposure (drug prescriptions) and dementia incidence. During follow-up, 13,786 (2.4%) of the study population developed dementia. We used time-dependent Cox proportional hazard models to study the effect of exposure on dementia incidence, controlling for the effects of age, sex, year, deprivation and smoking status. To account for multiple testing, we first analyzed a 50% household-area stratified random sample of the study population (discovery cohort), selected results with a Bonferroni-corrected p-value, re-run the analysis of ‘significantly’ associated drugs in the remaining 50% (validation cohort) and once again selected results with a Bonferroni-corrected p-value. We displayed the results (hazard ratio and p-value) from the complete cohort in several stratified volcano-plots and clinically reviewed the findings to identify potential pathways of effect. Results 177/733 (24%) of the analysed drugs were significantly associated with dementia incidence. Of those, 7 were for neurodegenerative conditions that can cause dementia, 14 were for vascular diseases, 13 for diabetes, 16 for depression and 39 for symptoms or complications of dementia. Only four, all travel-related vaccines, were associated with a lower dementia incidence. Some drugs associated with an increased hazard of dementia clustered around several unexpected indications, including: gastro-oesophageal reflux disease, altered bowel habit, lower urinary tract symptoms and infections, anxiety, sleep disturbance, pain and nausea/vertigo. Discussion By grouping drugs by indication, we identified several drugs with a potential of having a direct association with increased risk of dementia. We also identified drugs which are related to (known) risk factors for dementia, including those prescribed for cardiovascular disease and diabetes. The effect of travel-related vaccines is puzzling and might be more related to a preventative association of travelling with dementia incidence. Most interestingly, we identified several drugs which might have been prescribed as a consequence of a preclinical, non-cognitive syndrome in dementia.

Case presentation: 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. Conclusions: 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.

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. Electronic supplementary material The online version of this article (10.1007/s10654-019-00499-1) contains supplementary material, which is available to authorized users.

Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

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.

Altres ajuts: The Stroke Genetics Network (SiGN) study was funded by a cooperative agreement grant from the US National Institute of Neurological Disorders and Stroke (NINDS), NIH (U01 NS069208 and R01 NS100178). SAHLSIS was supported by the Swedish Heart and Lung Foundation (HLF-20160316), the Swedish Research Council (K2014-64X-14605-12-5), the Swedish Stroke Association, the Swedish state (under the "Avtal om Läkarutbildning och Medicinsk Forskning, ALF") (ALFGBG-720081). Australian Stroke Genetics Collaboration study was supported by the National Health and Medical Research Council, Australia. Stroke Pharmacogenomics and Genetics group was supported by Invictus plus network, Generation project, and Miguel Servet programme from Instituto de Salud Carlos III, GODs project and Epigenesis project from Marató de TV3 Foundation and Agaur from Generalitat de Catalunya Government. Arne Lindgren was supported by the Swedish Heart and Lung Foundation, Region Skåne, Skåne University Hospital, the Freemasons Lodge of Instruction EOS in Lund, Lund University, the Foundation of Färs & Frosta-one of Spar-banken Skåne's ownership Foundations, and the Swedish Stroke Association. Martin Söderholm was supported by grants from the Swedish Stroke Association, the Foundation of Färs & Frosta-one of Sparbanken Skåne's ownership Foundations, and the Swedish government (under the "Avtal om Läkarutbildning och Medicinsk Forskning, ALF"). Annie Pedersen was supported by grants from the Swedish government (under the "Avtal om Läkarutbildning och Medi-cinsk Forskning, ALF") and the Gothenburg Foundation for Neurological Research. Natalia Rost was in part supported by NIH-NINDS (R01NS086905 and R01NS082285). Daniel Strbian was supported by the Finnish Subsidiary Governmental Fund (VTR). The authors thank NINDS for funding the genotyping of patients included in the SiGN study (U01 NS069208 and R01 NS100178) and Sólveig Grétarsdóttir for genotyping a subsample of the SAHLSIS cohort. ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10.ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-Expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

BackgroundPopulation-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.MethodsWe 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.ResultsWe identified 18 articles, resulting in 27 measures of PPV and 14 of sensitivity. For PD, PPVs 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, PPVs ranged from 36-88% in hospital datasets, 40-74% in prescription datasets, and was 94% in mortality datasets. Sensitivities ranged from 15-73% in single datasets for PD and 43-63% in single datasets for parkinsonism.ConclusionsIn many settings, routinely-collected datasets generate good PPVs and reasonable sensitivities for identifying PD and parkinsonism cases. Further research is warranted to investigate primary care and medication datasets, and to develop algorithms that balance a high PPV with acceptable sensitivity.

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./n© 2015 American Academy of Neurology. Kristiina Rannikmäe is supported by the Edinburgh and Lothians Health Foundation REMIND Fund and Stroke Research and Amenities Endowments Fund; Cathie Sudlow is supported by the Scottish Funding Council; Gail Davies is supported by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1), BBSRC and Medical Research Council (MSRC). Tom Van Agtmael is supported by the Kidney Research UK project grant RP19/2012. Details of funding for the studies contributing to the ICH GWAS can be found in: Woo D, Falcone GJ, Devan WJ, et al. Meta-analysis of genome-wide association studies identifies 1q22 as a novel susceptibility locus for intracerebral hemorrhage. American Journal of Human Genetics 2014;pii: S0002-9297(14)00070-6. doi:10.1016/j.ajhg.2014.02.012. [Epub ahead of print]. Details of funding for the studies contributing to the ischaemic stroke GWAS can be found in: Traylor M, Farrall M, Holliday EG, et al. Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurology 2012;11:951-962. Details of funding for the studies contributing to the WMH in ischaemic stroke GWAS can be found in: Adib-Samii P, Rost N, Traylor M, et al. 17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischaemic Stroke, But Not With Lacunar Stroke Status. Stroke 2013;44:1609-1615. Details of funding for the studies contributing to the WMH in population GWAS can be found in: Fornage M, Debette S, Bis JC, et al. Genome-Wide Association Studies of Cerebral White Matter Lesion Burden: The CHARGE Consortium. Annals of Neurology 2011;69:928-939. Martin Dichgans is supported by the Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain); Guido J Falcone is supported by the NIH / NINDS grant P50NS061343; Chistopher D Anderson is supported by the American Brain Foundation Clinical Research Training Fellowship, NIH-NINDS K23NS086873, Massachusetts General Hospital Institute for Heart, Vascular, and Stroke Care SPARK award; Jonathan Rosand is supported by the NIH / NINDS grant R01NS059727.

The Republic of Estonia (Estonian: Eesti Vabariik ) is in the Baltic region of Northern Europe (figures 1⇓–3). This wonderful country (no bias) is bordered to the north by the Gulf of Finland, to the west by the Baltic Sea, to the south by Latvia and to the east by Russia and Lake Peipsi (not ‘Lake Pepsi’ as thought of by at least one of my British friends!). Across the Baltic Sea lies Sweden in the west and a short ferry ride takes you to Finland in the north, just 80 km away.1 The territory of Estonia covers about 45 000 km2, and our population is just over 1.3 million.2 Figure 1 The flag of Estonia. Figure 2 Estonia. Figure 3 Location of Estonia in Europe. Estonia became independent from the Soviet Union in 1991, but is more strongly influenced by Nordic tastes and traditions. It has been a European Union member state since 2004. The local currency is the euro, though some of us still miss the old ‘kroon’! The Estonian language is a Finno-Ugric language that closely resembles Finnish, and is very different from the Latvian and Russian languages spoken by our bordering neighbours. English is also widely spoken. Our claims to fame include Tallinn being the ‘stag-party capital’ for a few years in the early 2000s (thankfully more recently challenged by Riga) and of course winning the Eurovision Song Contest in 2001 (surely you remember the Dave Benton and Tanel Padar duo performing ‘Everybody’?). But on a more serious note, we have always been a ‘singing’ nation: we have a long ongoing tradition dating back to 1869 of having national song festivals (figure 4). These are among the largest amateur choral events in the world, held once every five years, in which >30 000 singers perform to an audience of 80 000. …

BackgroundWe describe a patient co-presenting with epilepsia partialis continua (EPC), disseminated tuberculosis (TB), and hemophagocytic lymphohistiocytosis (HLH).CaseA 54-year-old lady presented with facial twitching, breathlessness, and 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 EPC was made (video provided). CT imaging of the chest and serous fluid analyses were consistent with a diagnosis of disseminated Mycobacterium tuberculosis, with a left motor strip tuberculoma evident on post-contrast MRI brain. An additional diagnosis of HLH was made following the identification of pancytopenia and hyperferritinaemia on peripheral blood, with hemophagocytosis evident on bone marrow investigation (pathology slides provided). She was extremely unwell and hospitalised for six months, including two admissions to intensive care for invasive ventilation. She was treated successfully with high doses of antiepileptic drugs, 12 months of oral anti-TB therapy, and chemotherapy with eight weeks of etoposide and dexamethasone for HLH, followed by 12 months of ciclosporin and prednisolone.ConclusionsPresentation with this triad is rare – to our knowledge, this is the first documented case. A lack of evidence surrounding the co-expression of this triad may represent absolute rarity or, more likely, clinical failure to recognise the triad (resulting in early death from untreated TB/HLH). Therefore, the case helps improve education around how such a patient may present and be managed.

Objectives Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the e4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-e4 and e2 are associated with lobar ICH. The generally accepted explanation is that APOE-e4 promotes vascular amyloid deposition, while APOE-e2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects. Methods We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of e4-containing (e4+) and e2-containing (e2+) genotypes on progression to severe CAA. Results Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of e4+ genotypes with severe CAA (e4+ vs e4-: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For e2+ versus e2- genotypes, there was no significant association, but the very small number of participants with e2+ genotypes (22) precluded reliable estimates. Conclusions We found a possible association of severe CAA with APOE-e4 but not APOE-e2. However, our findings do not exclude a biologically meaningful association between APOE-e2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.

Introduction: In observational studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of spontaneous intracerebral hemorrhage (ICH). Common DNA sequence variants within the cholesteryl ester transfer protein ( CETP ) gene decrease CETP protein activity and increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development to combat coronary artery disease. Hypothesis: Common CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH. Methods: We performed a two-stage case-control genetic association study in Caucasians. The discovery phase utilized data on 12 independent loci within CETP (+/- 50 kilobases) from 3 genome-wide association studies of ICH. Replication involved direct genotyping in 5 additional studies. We also constructed a genetic risk score with 7 independent CETP variants and tested it for association with HDL-C and ICH risk. We used principal component analysis to account for population structure and a Bonferroni-adjusted p Results: The discovery phase included 1149 ICH cases (43% lobar hemorrhages) and 1238 controls. Twelve variants were nominally associated (p-4 ) and no heterogeneity across studies (I 2 =0%). This association was replicated in 1625 cases (43% lobar hemorrhages) and 1845 controls (OR 1.12, 95%CI 1.02-1.24; p=0.03). A genetic score of independent CETP variants known to increase HDL-C by ~2.85 mg/dL was strongly associated with ICH risk (OR 1.86, 95%CI 1.44-2.40; p=1.4x10 -6 ). Conclusion: 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 is warranted.

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 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3'-UTR (rs2023938; P = 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.

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.

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.

The study aimed to use functional magnetic resonance imaging to ascertain changes in sensorimotor system function in patients with hereditary spastic paraplegia and to correlate it with severity of spasticity and paresis.Tartu University Hospital, Tartu, Estonia.Nine patients with autosomal-dominant pure HSP and 14 age- and sex-matched healthy controls were investigated with a 1.5T fMRI scanner during flexion/extension of the right-hand fingers and right ankle. Images were analysed with a general linear model and Statistical Parametrical Mapping software. Highest Z-scores were identified from probability maps, and weighted laterality indices were calculated using combined bootstrap/histogram analysis; these were correlated with clinical severity of spasticity and paresis.During hand movements, clusters located in contralateral primary sensorimotor and premotor areas activated in both controls and patients. Bilateral activation occurred in the supplementary motor area, parietal operculum and cerebellum (predominantly ipsilateral). During the ankle task, bilateral activation was noted in the primary sensorimotor area, supplementary motor area and cerebellum. Activation clusters in HSP patients were smaller than those in controls in the sensorimotor area, especially during the ankle task, and more pronounced ipsilaterally in cerebellum both during hand and ankle motor tasks. Spasticity was significantly associated with contralateral activation in the sensory area and correlated negatively with the highest Z-scores in Brodmann areas 1-2-3 and 4.Our results suggest changes in cortical sensorimotor network function in patients with HSP compared with healthy subjects. Lower activation in patients might reflect damage to the corticospinal tract, be influenced by compensatory mechanisms, and/or be a reflection of neurorehabilitation.

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 x 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 x 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.

Background and Purpose— NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods— Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. Results— The distribution of pathogenic categories varied by study, age, sex, and race ( P Conclusions— This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

Summary Background The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13–1·30, p=4·50 × 10 −8 ; joint OR 1·19, 1·12–1·26, p=1·30 × 10 −9 ). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29–1·49, p=3·26 × 10 −19 ; joint OR 1·37, 1·30–1·45, p=2·79 × 10 −32 ) and ZFHX3 (first stage OR 1·19, 1·11–1·27, p=2·93 × 10 −7 ; joint OR 1·17, 1·11–1·23, p=2·29 × 10 −10 ) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18–1·42, p=3·50 × 10 −8 ; joint OR 1·24, 1·15–1·33, p=4·52 × 10 −9 ) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2 , which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12–1·28, p=6·82 × 10 −8 ; joint OR 1·17, 1·11–1·23, p=2·92 × 10 −9 ). Other loci associated with stroke in previous studies, including NINJ2 , were not confirmed. Interpretation Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding US National Institute of Neurological Disorders and Stroke, National Institutes of Health.