Causal relationship between hypertension and epilepsy: a mendelian randomization study

Establishing new approaches for the prevention and treatment of stroke relies on identifying modifiable risk factors that contribute to the development of this complex disease. Mendelian randomization (MR) studies, analogous to naturally occurring randomized trials, can assess causality of potentially modifiable biomarkers and offer new insights into biological pathways. Stroke is the second leading cause of death worldwide and the chief determinant of long-term disability. Stroke is a heterogeneous disease arising from several distinct underlying pathologies and is typically classified as ischemic or hemorrhagic, and further subclassified using imaging data. Ischemic stroke (IS), including its 3 main subtypes: small vessel disease, large vessel disease, and cardioembolic stroke, accounts for ≈80% of stroke and is the result of an interrupted blood supply, leading to localized areas of ischemia in the brain. Small vessel disease may be a consequence of nonatherosclerotic, as well as atherosclerotic, mechanisms that result in an occlusion of the small perforating arteries, whereas large vessel disease results from occlusions or emboli from plaque rupture in larger vessels, such as a carotid artery. Cardioembolic stroke arises typically from emboli from the heart. By contrast, hemorrhagic stroke is a consequence of intracerebral hemorrhage (bleeding into the brain) or subarachnoid hemorrhage (bleeding into the subarachnoid space). These diverse stroke subtypes have distinct underlying pathologies reflecting different risk factor distributions. MR studies, using genetic variants as instrumental variables, afford a powerful approach to assessing causality of risk factors and avoid biases inherent in observational studies, including confounding and reverse causation. This review considers the contribution of MR studies to stroke epidemiology and their relevance to understanding risk factors and new therapeutic targets for stroke. Meta-analyses of large prospective studies have enhanced our knowledge of classical and emerging risk factors for stroke.1–4 Classical risk factors for stroke include nonmodifiable characteristics, …

### Case A 68-year-old right-hand-dominant man was brought to the hospital because of a speech disturbance and right arm and leg weakness. He awoke with these deficits and was last known to be symptom-free when retiring to bed the previous evening 8 hours earlier. His past medical history was notable for coronary heart disease, the patient having underwent coronary artery bypass surgery 7 years previously for unstable angina, but he had no known history of myocardial infarction. He also had hypertension and hyperlipidemia, and smoked 1 pack of cigarettes daily for more than 40 years. He had no history of calf claudication. His hypertension was being treated with a diuretic and β-adrenergic receptor blocker. He was also prescribed 325 mg of aspirin daily and an HMG CoA-reductase inhibitor (statin); however, his wife remarked that he often forgot to take his medications. His last total cholesterol was 240 mg/dL, with LDL cholesterol of 130 mg/dL. He had a strong family history of coronary heart disease after the age of 50. He had no known drug allergies. #### Physical Examination The patient’s blood pressure was 195/100 mm Hg in both arms, with a regular pulse of 90 bpm. His weight was 225 lb (body mass index: 31.4 kg/m2). His lungs were clear to auscultation. Cardiac examination showed a laterally displaced point of maximum impulse with an S4 gallop and a soft nonradiating systolic murmur at the base. His abdomen was obese without organomegaly and no abdominal bruits were detected. He had no rashes and no joint deformities. The left superficial temporal artery pulse was stronger than the right. There were soft bilateral anterior cervical bruits, left louder than right, but no supraclavicular bruits. There were bilateral femoral bruits. Radial pulses were 2+ and symmetric. Dorsalis pedis and posterior tibial pulses were 1+. …

Blood Pressure Goals: How Low Is Safe in CKD?

ObjectivePrevious studies have shown that human immunodeficiency virus (HIV) infection is associated with hypertension; however, the results of these studies are affected by a variety of confounding factors. There is no definite evidence to prove a causal relationship between these two factors. This study aimed to investigate the causal relationship between HIV infection and hypertension.MethodsA two-sample Mendelian randomization (MR) study was conducted using genome-wide association study (GWAS) statistics published online. The data were collected mainly from the OpenGWAS and FinnGen databases. The HIV database contained 357 HIV patients and 218,435 control patients; the hypertension database contained 54,358 patients and 408,652 control patients; and the blood pressure database contained 436,424 samples. Random effect inverse variance weighting (IVW) was used as the main analysis method, weighted median and Mr-Egger analysis methods were used to ensure the accuracy of the results, and Cochran’s Q test and Mr-Egger regression methods were used to detect heterogeneity and correct multiple horizontal effects. Finally, the leave-one-out method was used to analyse the reliability of the test results. In order to further verify the research results, different databases were used and the same statistical method was used for a replication analysis. In order to prevent false positive results caused by multiple tests, Bonferroni correction is used to correct the statistical results.ResultsAfter screening, a total of 9 SNPs (single-nucleotide polymorphisms) were selected as the instrumental variable (IV) used in this study. The IVW MR analysis results showed a causal relationship between HIV infection and the risk of hypertension (IVW: OR = 1.001, P = 0.03). When systolic blood pressure was the outcome, the IVW method results were positive (OR = 1.004, P = 0.01280), and when diastolic blood pressure was the outcome, the weighted median method results were positive (OR = 1.004, P = 0.04570). According to the sensitivity analysis, the results of this study were unlikely to be affected by heterogeneity and horizontal pleiotropy. The leave-one-out analysis showed that the results of this study did not change significantly with the elimination of a single SNP. In replication analysis, when diastolic blood pressure was taken as the outcome, the weighted median method was positive (OR = 1.042, P = 0.037). Sensitivity analysis shows that there is heterogeneity, but there is no horizontal pleiotropy. The leave-one-out analysis showed that the results of this study did not change significantly with the elimination of a single SNP.ConclusionAs the first exploratory study using MR method to study the causal relationship between HIV infection and hypertension and blood pressure, this study found that HIV infection may increase systolic and diastolic blood pressure and increase the risk of hypertension. PLWH, as a high-risk group of cardiovascular and cerebrovascular diseases, should prevent the occurrence of hypertension in order to further improve their quality of life. However, this study also has some limitations. The results of the relationship between HIV infection and hypertension and blood pressure may be affected by the lack of statistical efficacy. In order to further confirm this conclusion, more large-scale RCT or genetic studies should be carried out.

Observational studies have indicated that high blood pressure (BP) may be a risk factor to frailty. However, the causal association between BP and frailty remains not well determined. The purpose of this bi-directional two-sample Mendelian randomization (MR) study was to investigate the causal relationship between BP and frailty. Independent single nucleotide polymorphisms (SNPs) strongly (P < 5E-08) associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) were selected as instrumental variables. Two different published genome-wide association studies (GWAS) on BP from the CHARGE (n = 810,865) and ICBP (n = 757,601) consortia were included. Summary-level data on frailty index (FI) were obtained from the latest GWAS based on UK Biobank and Swedish TwinGene cohorts (n = 175,226). Inverse variance weighted (IVW) approach with other sensitivity analyses were used to calculate the causal estimate. Using the CHARGE dataset, genetic predisposition to increased SBP (β = 0.135, 95% CI = 0.093 to 0.176, P = 1.73E-10), DBP (β = 0.145, 95% CI = 0.104 to 0.186, P = 3.14E-12), and PP (β = 0.114, 95% CI = 0.070 to 0.157, p = 2.87E-07) contributed to a higher FI, which was validated in the ICBP dataset. There was no significant causal effect of FI on SBP, DBP, and PP. Similar results were obtained from different MR methods, indicating good stability. There was potential heterogeneity detected by Cochran's Q test, but no horizontal pleiotropy was observed in MR-Egger intercept test (P > 0.05). These findings evinced that higher BP and PP were causally associated with an increased risk of frailty, suggesting that controlling hypertension could reduce the risk of frailty.

T HE pathophysiology of head injury results from a complex set of interrelated and interdependent factors such as concussion, changes in intracranial pressure and cerebral blood flow, cerebral edema, and cerebrospinal production and absorption. This report is primarily concerned with alterations in cerebral blood flow during acute compression of the brain and in the hours thereafter. While other studies have been carried out on blood flow during various types of head injury and increased intracranial pressure, few have investigated the beneficial effects of increasing blood flow during poor flow conditions. This investigation utilizes our model of extradural compression previously described. 1~ The model furnishes a relatively controlled means of altering brain compression, brain distortion, and intracranial pressure. It also lends itself to greater reliability in studies of mortality and morbidity in a series of animals. This study was carried out in three parts: 1. Changes in cerebral blood flow and arteriovenous oxygen difference induced by extradural compression. 2. Alterations in cerebral blood flow with isovolemie hemodilution. 3. Effects of hemodilution and hemodilution plus hyperbaric oxygenation on mortality and morbidity following cerebral injury.

The aim of the study was to analyze changes of systolic and diastolic blood pressure values over five and ten years separately boys and girls and to estimate correlation between them. Three age groups from 8 centers in Serbia were evaluated: Group 1: 10 year old patients, Group 2: 15 year old and Group 3: 20 year old. Group with normal blood pressure values, prehypertensive and hypertensive group were analyzed. Regarding the period of follow-up we analyzed: 10/15 years period-children between 10 and 15 years, 15/20 years period-children between 15 and 20 years, and 10/20 years period-children between 10 and 20 years. Significant increase of diastolic blood pressure was noticed for both genders in 10/15 years period of prehypertensive population, while in hypertensive children, boys showed decline in frequency for systolic and diastolic blood pressure and girls only for diastolic. In 15/20 years period there was significant decrease of prehypertensive and significant increase of hypertensive diastolic blood pressure frequency. In 10/20 years period significant reduction in frequency of prehypertensive systolic blood pressure was noticed, while only hypertensive group of boys showed significant reduction regarding systolic blood pressure frequency. Prehypertensive diastolic and hypertensive systolic blood pressure fluctuations are more related to age.

This study aims to evaluate the causal association of blood pressure (BP) with cardiovascular diseases (CVDs). Two-sample Mendelian randomization was performed using a large genome-wide association study (n=299 024) and the UK Biobank cohort (n=375 256). We identified 327 and 364 single-nucleotide polymorphisms strongly and independently associated with systolic BP and diastolic BP, respectively, as genetic instruments to assess the causal association of BP with total CVD, CVD mortality, and 14 cardiovascular conditions. Nonlinearity was examined with nonlinear instrumental variable assumptions. Genetically predicted BP was significantly positively associated with total CVD (systolic BP, per 10 mm Hg: odds ratio [OR], 1.32 [95% CI, 1.25-1.40]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.15-1.26]). Similar positive causal associations were observed for 14 cardiovascular conditions including ischemic heart disease (systolic BP, per 10 mm Hg: OR, 1.33 [95% CI, 1.24-1.41]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.14-1.27]) and stroke (systolic BP, per 10 mm Hg: OR, 1.35 [95% CI, 1.24-1.48]; diastolic BP, per 5 mm Hg: OR, 1.20 [95% CI, 1.12-1.28]). Nonlinearity Mendelian randomization test demonstrated linear causal association of BP with these outcomes. Consistent estimates were observed in sensitivity analyses, suggesting robustness of the associations and minimal horizontal pleiotropy. The linear positive causal association of BP and CVD was consistent with previous findings that lower BP is better, thus consolidating clinical knowledge on hypertension management in CVD risk reduction.

PurposeSeveral antihypertensive drugs have been used for the treatment of glaucoma. However, the effect of hypertension and antihypertensive drugs on glaucoma is still unclear.MethodsLeveraging large-scale genome-wide association study summary statistics for glaucoma (Ncase = 4737, Ncontrol = 458,196), blood pressure (BP) (N = 422,771), and intraocular pressure (IOP) (N = 31,269), the genetic correlation and causal relationship of genetically assessed IOP, systolic blood pressure (SBP), diastolic blood pressure (DBP), and 12 types of antihypertensive drugs with glaucoma were evaluated using linkage disequilibrium score (LDSC) regression, univariate mendelian randomization (MR), and multivariable MR.ResultsLDSC results showed a suggestive association of glaucoma with SBP (Rg = 0.12, P = 0.0076) and DBP (Rg = 0.17, P = 0.02). In univariate MR, genetically elevated BP in participants was not identified to lead to an increased glaucoma risk (SBP: odds ratio [OR], 1.05 [95% confidence interval {CI}, 0.91–1.21]; P = 0.52; DBP: OR, 1.07 [95% CI, 0.93–1.23]; P = 0.34). The results of univariate MR were replicated in multivariable MR (SBP: OR, 0.95 [95% CI, 0.71–1.29]; P = 0.75; DBP: OR, 1.13 [95% CI, 0.85–1.51]; P = 0.41). Furthermore, there was insufficient evidence to suggest that antihypertensive drugs were associated with glaucoma.ConclusionsTogether, controlling BP may not help prevent and treat glaucoma, and antihypertensive drugs may neither treat nor worsen glaucoma.Translational RelevanceTreating with antihypertensive drugs should not be used as an intervention for patients with glaucoma.

sponsorship: The European Union (HEALTH-F7-2011-278249 EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher Grant 294713 EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.0880.13) currently support the Studies Coordinating Centre (Leuven, Belgium). (European Union|HEALTH-F7-2011-278249 EU-MASCARA, European Union|HEALTH-F7-305507 HOMAGE, European Union (European Research Council)|294713 EPLORE, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0881.13, Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium|G.0880.13)

Introduction Increased arterial stiffness is a powerful independent risk factor for adverse cardiovascular events. While pulse wave velocity has been used extensively as a biomarker of vascular health reflecting functional and structural arterial changes, its use in clinical practice was limited. The Arterial Stiffness Index (ASI) simplifies the assessment of arterial stiffness using a pulse waveform obtained at the finger with an infrared sensor with BP measured using an automated device. Age and raised blood pressure (BP) are major contributors to increased arterial stiffness, but time trajectories of ASI in the general population and optimal BP values to reduce arterial stiffening are scarcely known. Purpose To establish temporal changes of ASI and identify BP values associated with longer-term improvement of arterial stiffness. Methods The study analysed data from UK Biobank (baseline n=154,684, median age 54, interquartile range (IQR) [40-72] years; 52% female; 91% white, 28% hypertension). ASI was measured using PulseTrace PCA2 device (CareFusion, USA) at baseline with measurements repeated in 4617 individuals after a median follow up of 3.0, IQR [2.8-3.3] years. BP was measured during the same time points. Multivariable (adjusted for age, sex, diabetes, and use of BP-lowering drugs) linear regression was used to determine the association of BP with baseline and the association of BP and ASI changes during follow up. ROC analysis was used to determine BP values associated with improvement (reduction) of ASI during follow up. Continuous data are presented as median [IQR] and compared using Wilcoxon test. R software packages were used for analyses. Results At baseline, ASI (m/sec) was higher in those with systolic BP (SBP) &amp;gt;140 mmHg (9.60 [7.15-11.85] vs. 8.67 [6.77-10.70] for SBP ≤140 mmHg, p&amp;lt;0.001) and in those with diastolic BP (DBP) &amp;gt;90 mmHg (9.90 [7.48-12.16] vs 8.81 [6.78-10.90] for DBP ≤90 mmHg, p&amp;lt;0.001). Both SBP and DBP were independently associated with ASI at baseline (B±SE 0.08±0.02 and 0.79±0,29m, respectively; p&amp;lt;0.001 for both). During follow up, the population level SBP remained unchanged (change 0 [-8 - 8] mmHg), with some reduction in DBP (-1.0 [-6.0 - 3.5]) mmHg. SBP reduced in 2234 (48%) and DBP in 2517 (55%). ASI increased by 0.56 [-1.46 - 2.78] m/s, with ASI reduction observed in 1935 (42%). An increase in DBP but not in SBP was independently associated with an increase in ASI (B±SE DBP 0.04±0.01, p&amp;lt;0.001; SBP 0.007±0.006, p=0.22; DBP 0.04±0.007, p&amp;lt;0.001). The baseline BP was predictive of the magnitude of changes in ASI: SBP 132 mmHg (AUC 0.53, p=0.001) and DBP 83 mmHg (AUC 0.54, p&amp;lt;0.001). Conclusions Increased arterial stiffness is associated with higher BP, particularly with higher DBP. Raised ASI is reversible, providing BP is adequately controlled with optimal BP being &amp;lt;132/83 mmHg.

Introduction Blood pressure has been suggested as potential factor contributing to the increased risk of cardiovascular disease observed in women experiencing early menopause (&amp;lt;45 years). However, whether the association between early menopause and hypertension is causal remains unclear (1,2). Purpose To evaluate the observational and causal association between age at natural menopause (ANM) and blood pressure (BP) traits in Caucasian women. Methods Cross-sectional and one-sample Mendelian randomization (MR) study was conducted in 4451 postmenopausal women from two different cohort studies. Hypertension was defined as a systolic BP (SBP) ≥140 mmHg, and/or diastolic BP (DBP) ≥90 mmHg, and/or the use of antihypertensive medication. Multivariable linear and logistic regressions were implemented in the observational analysis. We calculated a weighted genetic risk score with 54 variants associated with ANM (GRS-ANM) (3). The genetic variants were previously identified in a genome wide association study (4), after that we implemented two-stage least squares in the one-sample MR. Estimates from all cohorts were pooled through meta-analysis Results The pooled analysis across cohorts showed early menopause, compared to menopause between 50–54 years, to be associated with lower DBP (β=−1.31 mmHg, 95% CI: −2.43; −0.18), while no association was found between other ANM categories and DBP. Similarly, the pooled analysis of both cohorts did not show an association of ANM with SBP, neither as a continuous variable nor by category. One year of later onset of menopause was associated with higher odds of developing hypertension (Odds ratio (OR): 1.02, 95% CI: 1:00; 1.04) while no association was found for the ANM categories and hypertension (Table 1). Results of the evaluation of MR assumption, supported their compliance, the GRS-ANM was associated with observed ANM and explained between 1.4% and 3.4% of the ANM variance in the included cohorts, F statistic values were among 11.15 and 40.63 (Figure 1). We found no association between GRS-ANM and SBP, DBP or hypertension (Table 1). Conclusion The present study does not support the hypothesis that early onset of menopause is associated with higher BP. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The CoLaus study was and is supported by research grants from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (grants 33CSCO-122661, 33CS30-139468 and 33CS30-148401).Zayne M. Roa-Díaz has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 801076, through the SSPH+ Global PhD Fellowship Programme in Public Health Sciences (GlobalP3HS) of the Swiss School of Public Health.

Background: The association of uromodulin and hypertension has been observed in clinical studies, but not proven by a causal relationship. We conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal relationship between uromodulin and blood pressure.Methods: We selected single nucleotide polymorphisms (SNPs) related to urinary uromodulin (uUMOD) and serum uromodulin (sUMOD) from a large Genome-Wide Association Studies (GWAS) meta-analysis study and research in PubMed. Six datasets based on the UK Biobank and the International Consortium for Blood Pressure (ICBP) served as outcomes with a large sample of hypertension (n = 46,188), systolic blood pressure (SBP, n = 1,194,020), and diastolic blood pressure (DBP, n = 1,194,020). The inverse variance weighted (IVW) method was performed in uUMOD MR analysis, while methods of IVW, MR-Egger, Weighted median, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were utilized on sUMOD MR analysis.Results: MR analysis of IVM showed the odds ratio (OR) of the uUMOD to hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.04 (95% Confidence Interval (CI), 1.03-1.04, P < 0.001); the effect sizes of the uUMOD to SBP are 1.10 (Standard error (SE) = 0.25, P = 8.92E-06) and 0.03 (SE = 0.01, P = 2.70E-04) in “ieu-b-38” and “ukb-b-20175”, respectively. The β coefficient of the uUMOD to DBP is 0.88 (SE = 0.19, P = 4.38E-06) in “ieu-b-39” and 0.05 (SE = 0.01, P = 2.13E-10) in “ukb-b-7992”. As for the sUMOD, the OR of hypertension (“ukb-b-14057” and “ukb-b-14177”) is 1.01 (95% CI 1.01–1.02, all P < 0.001). The β coefficient of the SBP is 0.37 (SE = 0.07, P = 1.26E-07) in “ieu-b-38” and 0.01 (SE = 0.003, P = 1.04E-04) in “ukb-b-20175”. The sUMOD is causally associated with elevated DBP (“ieu-b-39”: β = 0.313, SE = 0.050, P = 3.43E-10; “ukb-b-7992”: β = 0.018, SE = 0.003, P = 8.41E-09).Conclusion: Our results indicated that high urinary and serum uromodulin levels are potentially detrimental in elevating blood pressure, and serve as a causal risk factor for hypertension.

Introduction/Background: Renal denervation (RDN) is an emerging therapy shown to significantly reduce BP. Research Questions/Hypothesis: Impact of RDN on obese hypertensive Patients are unknown. Goals/Aims: Aim of our study to analyze the Impact of RDN on obese hypertensive patients. Methods/Approach: Patients were stratified into 2 groups Obese and non obese. Pre- and post-procedural. BP measurements were analyzed using repeated measures ANOVA to assess the changes in systolic (SYS) and diastolic (DIA) BP over time. Results/Data (descriptive and inferential statistics): This retrospective study included 50 hypertensive patients who underwent RDN with Symplicity Spyral from March 2023 to August 2024. The cohort had a mean age of 61.7 years. Pre-RDN mean SYS and DIA BP were 163.7 mmHg and 86.7 mmHg, respectively. The impact of renal denervation on blood pressure (BP) was examined in obese and non-obese groups. Initially, the non-obese group had a higher SYS BP (180 mmHg) compared to the obese group (160 mmHg). Post-RDN, SYS BP decreased to 145 mmHg in the non-obese group and to 140 mmHg in the obese group. Six months post-RDN, SYS BP stabilized at around 140 mmHg in both groups. RDN effectively reduced and maintained lower SYS BP in both groups over six months.The forest plot analysis showed that Dyslipidemia (DLP) significantly reduced the odds of achieving the SYS BP target (OR = 0.17, p = 0.036). Both regression lines showed strong fits (SYS BP: R 2 = 0.8277; DIA BP: R 2 = 0.997). Repeated Measures ANOVA indicated significant changes in SYS BP over time (p &lt; .001, η 2 p = 0.590), with significant interaction between time and BMI category (p = 0.038). Logistic regression analysis highlighted DLP as a significant predictor, reducing the likelihood of achieving the systolic BP Target (OR = 0.17, p = 0.036). Other factors like BMI, age, CKD, and EF% were not significant predictors. Conclusion(s): Renal denervation (RDN) with Symplicity Spyral effectively reduces blood pressure in both obese and non-obese individuals, with sustained improvements over six months. Dyslipidemia significantly decreases the likelihood of achieving target BP, while other factors such as BMI, age, chronic kidney disease (CKD), and ejection fraction percentage (EF%) are not significant predictors. These findings support the use of RDN as a viable intervention for managing hypertension, highlighting the importance of addressing dyslipidemia in hypertensive patients.

Background Observational evidence indicates that patients with atrial fibrillation (AF) are at a four- to fivefold increased risk of stroke. By two-sample mendelian randomization (MR), we have shown in our previous work that specifically the cardioembolic stroke subtype is caused by AF. This risk elevation is however variable and appears to be modulated by other risk factors such as hypertension traits and coronary artery disease (CAD). Purpose This study seeks to determine (1) whether genetic predisposition to cardioembolic stroke by AF is independent from modulators, and (2) whether the other stroke subtypes are causally linked with different exposures. Methods The associations between AF, hypertension traits, and CAD as exposures and stroke subtypes as outcomes were individually tested in a two-sample mendelian randomisation (MR) analysis using genetic instruments from publicly available genome-wide association studies (GWAS) in large cohorts. For atrial fibrillation, genetic instruments were obtained from the dataset by Nielsen et al. with 60,620 atrial fibrillation cases and 970,216 controls, collected from six contributing studies including the AFGen Consortium. Associations with stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67, 162 cases; 454, 450 controls). The genetic markers for hypertension traits were taken from a GWAS by Evangelou et al. which combines data from the UK Biobank (UKB) and the International Consortium of Blood Pressure (ICBP) with a total sample size of 757,601 individuals. Genetic instruments for CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls from 48 studies). Several MR regression methods such as MR-Egger regression and inverse-variance weighted regression as well as sensitivity analyses were applied. A multivariable MR model served to determine which of the exposures had an independent causal effect on each of the stroke subtypes. Results Atrial fibrillation turned out to be the sole independent causal risk factor for cardioembolic stroke with a beta coefficient of 0.75 (SE = ± 0.04; P = 8.59 x 10e-100) and an OR of 2.16 (1.97-2.27) in a multivariable model adjusted for AF, CAD, systolic blood pressure (SBP) and diastolic blood pressure. In this model, SBP and CAD were non-causative for cardioembolic stroke, but exhibited significant, albeit weak causal associations with small vessel stroke (SBP: OR 1.04 (1.02-1.06); CAD: OR 1.14 (1.02-1.28)) and large artery stroke (SBP: OR 1.09 (1.06-1.11); CAD: OR 1.59 (1.40-1.79). Conclusions Causality of the association between the cardioembolic stroke subtype and AF is independent from modulators such as SBP and CAD. However, SBP and CAD play a complementary role as causal exposures for small vessel and large artery stroke which in turn are not causally linked with AF.