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: 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 circulating levels of cytokines and growth factors are causally associated with stroke and its etiologic subtypes by conducting a two-sample Mendelian randomization (MR) study. Methods: Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study (GWAS) of 8,293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE GWAS dataset (67,162 cases; 454,450 controls) applying inverse-variance-weighted meta-analysis, weighted-median analysis, MR-Egger regression, and multivariable MR. The UK Biobank cohort was used as an independent validation sample (4,985 cases; 364,434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits using publicly available GWAS data. Results: Genetic predisposition to higher MCP-1 levels was associated with increased risk of

IMPORTANCE Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. OBJECTIVE To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS DATA SOURCES Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204 402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117 907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386 533 individuals); body mass index (BMI) (up to 322 154 individuals); and height (up to 253 280 individuals). DESIGN In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. RESULTS Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. CONCLUSIONS AND RELEVANCE This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strate...

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IMPORTANCE Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored. OBJECTIVE To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause. DATA SOURCES A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence. STUDY SELECTION A total of 12 323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed-or random-effects models were implemented. MAIN OUTCOMES AND MEASURES Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period. RESULTS The 14 studies included in the meta-analysis represented 67 714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67 434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54 715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52 736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48 894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses. CONCLUSIONS AND RELEVANCE Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting.

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Background: Studies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown. Methods: In a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R. Results: We identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque. Conclusions: We provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.

ObjectiveTo examine whether the Montreal Cognitive Assessment (MoCA) administered within 7 days after stroke predicts long-term cognitive impairment, functional impairment, and mortality.MethodsMoCA was administered to 274 patients from 2 prospective hospital-based cohort studies in Germany (n = 125) and France (n = 149). Cognitive and functional outcomes were assessed at 6, 12, and 36 months after stroke by comprehensive neuropsychological testing, the Clinical Dementia Rating (CDR) scale, the modified Rankin Scale (mRS), and Instrumental Activities of Daily Living (IADL) and analyzed with generalized estimating equations. All-cause mortality was investigated by Cox proportional hazard models. Analyses were adjusted for demographic variables, education, vascular risk factors, premorbid cognitive status, and NIH Stroke Scale scores. The additive predictive value of MoCA was examined with receiver operating characteristic curves.ResultsIn pooled analyses, a baseline MoCA score <26 was associated with cognitive impairment, defined by neuropsychological testing (odds ratio [OR] 5.30, 95% confidence interval [CI] 2.75–10.22) and by CDR score ≥0.5 (OR 2.53, 95% CI 1.53–4.18); functional impairment, defined by mRS score >2 (OR 5.03, 95% CI 2.20–11.51) and by IADL score <8 (OR 2.48, 95% CI 1.40–4.38); and mortality (hazard ratio 7.24, 95% CI 1.99–26.35) across the 3-year follow-up. Patients with MoCA score <26 performed worse across all prespecified cognitive domains (executive function/attention, memory, language, visuospatial ability). MoCA increased the area under the curve for predicting cognitive impairment (neuropsychological testing 0.81 vs 0.72, p = 0.01) and functional impairment (mRS score >2, 0.88 vs 0.84, p = 0.047).ConclusionEarly cognitive testing by MoCA predicts long-term cognitive outcome, functional outcome, and mortality after stroke. Our results support routine use of the MoCA in stroke patients.