Differences in causality between exposures and stroke subtypes: a mendelian randomisation approach

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, …

Epidemiological studies have reported inconsistent results of the association between celiac disease (CD) and cardiovascular diseases. Moreover, the causality remains largely unknown. Therefore, we aimed to investigate whether CD is causally associated cardiovascular diseases, including ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, coronary heart disease, myocardial infarction, angina, heart failure, atrial fibrillation, and venous thromboembolism using an mendelian randomization (MR) approach. Summary-level data for CD were derived from a large-sample genome-wide association study (GWAS) including 12,041 CD cases and 12,228 controls of European ancestry. The corresponding data for ischemic stroke (34,217 cases and 406,111 controls), large artery stroke (4,373 cases and 406,111 controls), cardioembolic stroke (7,193 cases and 406,111 controls), small vessel stroke (5,386 cases and 192,662 controls), coronary heart disease (22,233 cases and 64,762 controls), myocardial infarction (11,622 cases and 187,840 controls), angina (18,168 cases and 187,840 controls), heart failure (47,309 cases and 930,014 controls), atrial fibrillation (60,620 cases and 970,216 controls), and venous thromboembolism (9,176 cases and 209,616 controls) were obtained from the IEU GWAS database. We calculated the causal effect using the inverse variance weighted method. Sensitivity analyses and leave-one-out analyses were performed to ensure the consistency and robustness of causal estimates. The MR inverse variance weighted estimates indicated no causal effect of genetically predicted CD on ischemic stroke (OR = 1.001, 95% CI: 0.984-1.018), large artery stroke (OR = 1.003, 95% CI: 0.961-1.048), cardioembolic stroke (OR = 1.009, 95% CI: 0.977-1.042), small vessel stroke (OR = 1.023, 95% CI: 0.981-1.066), coronary heart disease (OR = 0.995, 95% CI: 0.977-1.013), myocardial infarction (OR = 0.994, 95% CI: 0.959-1.030), angina (OR = 1.006, 95% CI: 0.981-1.032), heart failure (OR = 0.999, 95% CI: 0.982-1.016), atrial fibrillation (OR = 1.000, 95% CI: 0.990-1.011), and venous thromboembolism (OR = 1.001, 95% CI: 0.971-1.032). Sensitivity analyses using the MR-Egger, weighted median, and simple mode methods yielded similar results. No evidence of horizontal pleiotropy was identified (MR Pleiotropy Residual Sum and Outlier global test and MR-Egger intercept with P > 0.05). Our findings do not support a causal contribution of CD itself to ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, coronary heart disease, myocardial infarction, angina, heart failure, atrial fibrillation, and venous thromboembolism risk.

Background: In observational studies, the self-reported walking pace has been associated with the risk of cardiovascular diseases (CVD). However, whether those associations indicate causal links remains unclear. We performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of walking pace on several CVD outcomes, including atrial fibrillation (AF), heart failure (HF), any stroke, ischemic stroke (IS), and IS subtypes. Methods: Genetic variants associated with self-reported walking pace were selected as instrumental variables (IVs) from the latest genome-wide association studies (GWAS). Summary-level data for outcomes were obtained from the corresponding GWAS and the FinnGen consortium. The random-effects inverse variance weighted (IVW) method was used as the main MR analysis, supplemented by replication analyses using data from the FinnGen. To explore the effect of pleiotropy due to adiposity-related traits, we further conducted MR analyses by excluding the adiposity-related IVs and regression-based multivariable MR adjusting for body mass index (BMI). Results: The MR results indicated significant inverse associations of self-reported walking pace with risks of AF [odds ratio (OR), 0.577; 95% confidence interval (CI), 0.442, 0.755; p = 5.87 × 10−5], HF (OR, 0.307; 95% CI, 0.229, 0.413; p = 5.31 × 10−15), any stroke (OR, 0.540; 95% CI, 0.388, 0.752; p = 2.63 × 10−4) and IS (OR, 0.604; 95% CI, 0.427, 0.853; p = 0.004) and suggestive inverse association of self-reported walking pace with cardioembolic stroke (CES) (OR, 0.492; 95% CI, 0.259, 0.934; p = 0.030). Similar results were replicated in the FinnGen consortium and persisted in the meta-analysis. However, there was no causality between walking pace and large artery stroke (OR, 0.676; 95% CI, 0.319, 1.434; p = 0.308) or small vessel stroke (OR, 0.603; 95% CI, 0.270, 1.349; p = 0.218). When excluding adiposity-related IVs and adjusting for BMI, the associations for HF and any stroke did not change substantially, whereas the associations for AF, IS, and CES were weakened. Conclusion: Our findings suggested that genetically predicted increasing walking pace exerted beneficial effects on AF, HF, any stroke, IS, and CES. Adiposity might partially mediate the effect of walking pace on AF, IS, and CES.

Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design. We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis. In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002). Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

Characteristics of Sleep-Disordered Breathing in Etiologic Subtypes of Minor-to-Moderate Acute Ischemic Stroke

Thrombosis and platelet activation play a central role in stroke pathogenesis, and antiplatelet and anticoagulant therapies are central to stroke prevention. However, whether haematological traits contribute equally to all ischaemic stroke subtypes is uncertain. Furthermore, identification of associations with new traits may offer novel treatment opportunities. The aim of this research was to ascertain causal relationships between a wide range of haematological traits and ischaemic stroke and its subtypes. We obtained summary statistics from 27 published genome-wide association studies of haematological traits involving over 375 000 individuals, and genetic associations with stroke from the MEGASTROKE Consortium (n = 67 000 stroke cases). Using two-sample Mendelian randomization we analysed the association of genetically elevated levels of 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells) and 49 haemostasis traits (including clotting cascade factors and markers of platelet function) with risk of developing ischaemic (AIS), cardioembolic (CES), large artery (LAS), and small vessel stroke (SVS). Several factors on the intrinsic clotting pathway were significantly associated (P < 3.85 × 10-4) with CES and LAS, but not with SVS (e.g. reduced factor VIII activity with AIS/CES/LAS; raised factor VIII antigen with AIS/CES; and increased factor XI activity with AIS/CES). On the common pathway, increased gamma (γ') fibrinogen was significantly associated with AIS/CES. Furthermore, elevated plateletcrit was significantly associated with AIS/CES, eosinophil percentage of white cells with LAS, and thrombin-activatable fibrinolysis inhibitor activation peptide antigen with AIS. We also conducted a follow-up analysis in UK Biobank, which showed that amongst individuals with atrial fibrillation, those with genetically lower levels of factor XI are at reduced risk of AIS compared to those with normal levels of factor XI. These results implicate components of the intrinsic and common pathways of the clotting cascade, as well as several other haematological traits, in the pathogenesis of CES and possibly LAS, but not SVS. The lack of associations with SVS suggests thrombosis may be less important for this stroke subtype. Plateletcrit and factor XI are potentially tractable new targets for secondary prevention of ischaemic stroke, while factor VIII and γ' fibrinogen require further population-based studies to ascertain their possible aetiological roles.

PurposeCardiac troponin I (cTnI) is a well-established biomarker for stroke prediction, especially in patients with heart diseases. However, the causal effect of circulating cTnI on stroke remains unclear.MethodsWe employed Mendelian Randomization (MR) analysis to determine the associations between genetically predicted circulating cTnI levels and stroke and its subtypes. Summary-level data for exposure and outcomes were generated from different genome-wide association studies. Single-nucleotide polymorphisms (SNPs) associated with circulating cTnI at genome-wide significance level (P < 5 × 10−8) were employed as instrumental variables (IVs). We used fixed-effect inverse-variance weighted (IVW) as the main method for pooling MR estimates. Sensitivity analyses and multivariable MR analyses were carried out to assess the robustness of the results.ResultsUsing the fixed-effects IVW method, we found that genetically elevated plasma cTnI levels may have a causal effect on the risk of cardioembolic stroke (CES) (odds ratio (OR), 1.58; 95% confidence interval (CI), 1.17–2.13; P = 0.003). Additional analyses including multiplicative random-effects (mre) IVW, weighted median, MR-Egger and MR-PRESSO yielded similar results, but with broader CIs that span 1.0. The total effect of cTnI on CES was attenuated by adjusting for the effect of atrial fibrillation (OR,1.26; 95% CI, 0.76–2.11; P = 0.371) and smoking (OR,1.53; 95% CI, 0.87–2.66; P = 0.137). In addition, we found no causal effect of cTnI on the risk of any stroke and other stroke subtypes, including any ischemic stroke, large artery stroke, cardioembolic stroke, small vessel stroke, and intracerebral hemorrhage. These results were consistent across sensitivity analyses.ConclusionThis study provides little evidence that increased serum cTnI levels lead to a higher risk of stroke.

Although emotional stress and adaptive behavior are known to influence cardiovascular health, direct evidence linking them to stroke remains limited. This study aims to clarify the associations between emotional stress, adaptive behaviors, and the risk of stroke. We conducted a two-sample Mendelian randomization analysis using data from the UK Biobank, the European Bioinformatics Institute, the Integrative Epidemiology Unit, and the FinnGen project. Indirect effects were estimated using the product of coefficients method. Low satisfaction with family relationships was associated with increased risks of all stroke and ischemic stroke. Mood swings were linked to higher risks of all stroke, ischemic stroke, and large-artery stroke, while feelings of tension were associated with large-artery stroke and small vessel stroke. Interestingly, nervousness was inversely associated with intracerebral hemorrhage risk. Participation in group leisure activities was associated with reduced risks of all stroke, ischemic stroke, and small vessel stroke. In contrast, several adaptive behaviors were linked to increased stroke risk, including vigorous physical activity (all stroke), summer outdoor activities (all stroke and ischemic stroke), winter outdoor activities (all stroke), and prolonged television watching (all stroke, ischemic stroke, and large-artery stroke). Mediation analyses suggested that hypertension, type 2 diabetes, atherosclerotic heart disease, and chronic ischemic heart disease may partially mediate these associations. The study provides genetic evidence supporting a potential causal relationship between emotional stress, adaptive behaviors, and stroke subtypes. Individuals can easily modify adaptive behaviors and manage emotional stress in their daily routines. Understanding these associations may inform future strategies for stroke prevention; however, due to limitations inherent in the current study design, our findings require further validation in large-scale prospective cohort studies.Graphical Emotional Stress, Adaptive behavior, and Stroke Risk. This study examined the genetic associations between emotional stress, adaptive behavior, and stroke risk, as well as the mediating effects of traditional stroke risk factors in these relationships.

Background and ObjectivesMigraine, stroke, and cervical artery dissection (CeAD) represent a triad of cerebrovascular disorders with pairwise comorbid relationships and vascular involvement. Larger samples and recent advances in methodology invite systematic exploration of their shared genetics.MethodsGenetic analyses leveraged summary statistics from genome-wide association studies of the largest available samples of each disorder, including subtypes of stroke (ischemic stroke, large artery stroke, small vessel stroke, and cardioembolic stroke) and migraine (with aura and without aura). For each pair of disorders, genetic correlation was assessed both on a genome-wide basis and within independent segments across the genome including known specific loci for each disorder. A cross-trait meta-analysis was used to identify novel candidate loci. Finally, potential causality of migraine susceptibility on stroke and CeAD was assessed by Mendelian randomization.ResultsAmong all pairs of disorders, genome-wide genetic correlation was observed only between CeAD and migraine, particularly MO. Local genetic correlations were more extensive between migraine and CeAD than those between migraine and stroke or CeAD and stroke and revealed evidence for novel CeAD associations at rs6693567 (ADAMTSL4/ECM1), rs11187838 (PLCE1), and rs7940646 (MRVI1) while strengthening prior subthreshold evidence at rs9486725 (FHL5) and rs650724 (LRP1). At known migraine loci, novel associations with stroke had concordant risk alleles for small vessel stroke at rs191602009 (CARF) and for cardioembolic stroke at rs55884259 (NKX2-5). Known migraine loci also revealed novel associations but with opposite risk alleles for all stroke, ischemic stroke, and small vessel stroke at rs55928386 (HTRA1), for large artery stroke at rs11172113 (LRP1), and for all stroke and ischemic stroke at rs1535791 and rs4942561 (both LRCH1), respectively. rs182923402 (near PTCH1) was a novel concordant locus for migraine and cardioembolic stroke. Mendelian randomization supported potential causal influences of migraine on CeAD (odds ratio [95% confidence interval] per doubling migraine prevalence = 1.69 [1.24–2.3], p = 0.0009) with concordant risk, but with opposite risk on large artery stroke (0.86 [0.76–0.96], p = 0.0067).DiscussionThe findings emphasize shared genetic risk between migraine and CeAD while identifying loci with likely vascular function in migraine and shared but opposite genetic risk between migraine and stroke subtypes, and a central role of LRP1 in all 3 cerebrovascular disorders.

BackgroundAppendicular lean mass (ALM) is a good predictive biomarker for sarcopenia. And previous studies have reported the association between ALM and stroke or Alzheimer’s disease (AD), however, the causal relationship is still unclear, The purpose of this study was to evaluate whether genetically predicted ALM is causally associated with the risk of stroke and AD by performing Mendelian randomization (MR) analyses.MethodsA two-sample MR study was designed. Genetic variants associated with the ALM were obtained from a large genome-wide association study (GWAS) and utilized as instrumental variables (IVs). Summary-level data for stroke and AD were generated from the corresponding GWASs. We used random-effect inverse-variance weighted (IVW) as the main method for estimating causal effects, complemented by several sensitivity analyses, including the weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Multivariable analysis was further conducted to adjust for confounding factors, including body mass index (BMI), type 2 diabetes mellitus (T2DM), low density lipoprotein-C (LDL-C), and atrial fibrillation (AF).ResultsThe present MR study indicated significant inverse associations of genetically predicted ALM with any ischemic stroke ([AIS], odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89–0.97; P = 0.002) and AD (OR, 090; 95% CI 0.85–0.96; P = 0.001). Regarding the subtypes of AIS, genetically predicted ALM was related to the risk of large artery stroke ([LAS], OR, 0.86; 95% CI 0.77–0.95; P = 0.005) and small vessel stroke ([SVS], OR, 0.80; 95% CI 0.73–0.89; P < 0.001). Regarding multivariable MR analysis, ALM retained the stable effect on AIS when adjusting for BMI, LDL-C, and AF, while a suggestive association was observed after adjusting for T2DM. And the estimated effect of ALM on LAS was significant after adjustment for BMI and AF, while a suggestive association was found after adjusting for T2DM and LDL-C. Besides, the estimated effects of ALM were still significant on SVS and AD after adjustment for BMI, T2DM, LDL-C, and AF.ConclusionsThe two-sample MR analysis indicated that genetically predicted ALM was negatively related to AIS and AD. And the subgroup analysis of AIS revealed a negative causal effect of genetically predicted ALM on LAS or SVS. Future studies are required to further investigate the underlying mechanisms.

A true discrepancy between the effect of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on cardiovascular (CV) outcomes remains unclear. This study performed two-sample Mendelian randomization (MR) using genetic instruments that exclusively predict SBP, DBP or both to dissect the independent effect of SBP and DBP on a range of CV outcomes. Genetic predisposition to higher SBP and DBP was associated with increased risk of coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Genetically proxied SBP exclusively was associated with CAD (OR 1.18, 95% CI: 1.03–1.36, per 10 mmHg), stroke (1.44[1.28–1.62]), ischemic stroke (1.49[1.30–1.69]), HF (1.41[1.20–1.65]), AF (1.28[1.15–1.43]), and T2DM (1.2[1.13–1.46]). Genetically proxied DBP exclusively was associated with stroke (1.21[1.06–1.37], per 5 mmHg), ischemic stroke (1.24[1.09–1.41]), stroke small-vessel (1.35[1.10–1.65]) and CAD (1.19[1.00–1.41]). Multivariable MR using exclusive SBP and DBP instruments showed the predominant effect of SBP on CAD (1.23[1.05–1.44], per 10 mmHg), stroke (1.39[1.20–1.60]), ischemic stroke (1.44[1.25–1.67]), HF (1.42[1.18–1.71]), AF (1.26[1.10–1.43]) and T2DM (1.31[1.14–1.52]). The discrepancy between effects of SBP and DBP on outcomes warrants further studies on underpinning mechanisms which may be amenable to therapeutic targeting.

Previous studies of obstructive sleep apnea (OSA) in relation to stroke have been noted. However, the exact causality remains to be clearly defined. We aimed to adopt a two-sample Mendelian randomization study to investigate the causal effects of OSA on stroke and its subtypes. A two-sample Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of OSA on stroke and its subtypes, including, based on publicly genome-wide association studies (GWAS) databases. The inverse variance weighted (IVW) method was used as the main analysis. MR-Egger regression, weighted mode, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed methods and were adopted as supplementary analysis to ensure the robustness of the results. Genetically predicted OSA was not related to the risk of stroke (odds ratio (OR), 0.99, 95% CI, 0.81-1.21, p = 0.909), and its subtypes, ischemic stroke (IS) (OR, 1.01, 95% CI, 0.82-1.23, p = 0.927), large vessel stroke (LVS) (OR, 1.05, 95% CI, 0.73-1.51, p = 0.795), cardioembolic stroke (CES) (OR, 1.03, 95% CI, 0.74-1.43, p = 0.855), small vessel stroke (SVS) (OR, 1.13, 95% CI, 0.88-1.46, p = 0.329), lacunar stroke (LS) (OR, 1.07, 95% CI, 0.74-1.56, p = 0.721) as well as intracerebral hemorrhage (ICH) (OR, 0.37, 95% CI = 0.09, 1.48, p = 0.160) (Wald ratio method). Other supplementary MR methods also confirmed similar results. There may be no direct causal relationship between OSA and stroke or its subtypes.

Assessing whether modifiable risk factors are causally associated with stroke risk is important in planning public health measures, but determining causality can be difficult in epidemiological data. We evaluated whether modifiable lifestyle factors including educational attainment, smoking, and body mass index are causal risk factors for ischemic stroke and its subtypes and hemorrhagic stroke. We performed 2-sample and multivariable Mendelian randomization to assess the causal effect of 12 lifestyle factors on risk of stroke and whether these effects are independent. Genetically predicted years of education was inversely associated with ischemic, large artery, and small vessel stroke, and intracerebral hemorrhage. Genetically predicted smoking, body mass index, and waist-hip ratio were associated with ischemic and large artery stroke. The effects of education, body mass index, and smoking on ischemic stroke were independent. Our findings support the hypothesis that reduced education and increased smoking and obesity increase risk of ischemic, large artery, and small vessel stroke, suggesting that lifestyle modifications addressing these risk factors will reduce stroke risk.

In recent years, the incidence rates of rheumatoid arthritis (RA) and heart disease (HD) have noticeably increased worldwide. Previous studies have found that patients with RA are more likely to develop HD, while the cause and effect have still remained elusive. In this study, Mendelian randomization (MR) analysis was used to indicate whether there was a potential association between RA and HD. Data of RA, ischemic heart disease (IHD), myocardial infarction (MI), atrial fibrillation (AF), and arrhythmia were based on the genome-wide association study (GWAS) dataset. No disease group was intersected. Inverse-variance weighted (IVW) method was used to calculate MR estimates, and sensitivity analysis was performed. The primary MR analysis showed that genetic susceptibility to RA was significantly associated with the risk of IHD and MI, rather than with AF and arrhythmia. Besides, there was no heterogeneity and horizontal pleiotropy between the primary and replicated analyses. There was a significant correlation between RA and the risk of IHD (odds ratio (OR), 1.0006; 95% confidence interval (CI), 1.000244-1.00104; P = 0.001552), meanwhile, there was a significant correlation between RA and the risk of MI (OR, 1.0458; 95% CI, 1.07061-1.05379; P = 0.001636). The results were similar to those of sensitivity analysis, and the sensitivity analysis also verified the conclusion. Furthermore, sensitivity and reverse MR analyses suggested that no heterogeneity, horizontal pleiotropy or reverse causality was found between RA and cardiovascular comorbidity. RA was noted to be causally associated with IHD and MI, rather than with AF and arrhythmia. This MR study might provide a new genetic basis for the causal relationship between RA and the risk of CVD. The findings suggested that the control of RA activity might reduce the risk of cardiovascular disease.

BackgroundPrevious epidemiological evidence has suggested that frailty status might be associated with cardiovascular diseases (CVDs). However, the exact causality remains unestablished. In this study, we employed Mendelian randomization and sought to investigate the potential causality in association of frailty index (FI) with cardiovascular outcomes [coronary artery disease (CAD), myocardial infarction (MI), atrial fibrillation (AF), and heart failure (HF)].MethodsIndependent single nucleotide polymorphisms (SNPs) at genome-wide significance for FI were obtained from a recent genome-wide association study (GWAS) meta-analysis of European descent (n=175,226). The association of these SNPs with CVDs was examined in summary statistics from corresponding GWASs of European descent (CAD: 184,305 cases and 60,801 controls; MI: 184,305 cases and 43,676 controls; AF: 1,030,836 cases and 60,620 controls; and HF: 977,323 cases and 47,309 controls). Replication analyses were performed using GWAS datasets from FinnGen.ResultsIn the meta-analysis of inverse-variance weighted estimates from different data sources, genetically determined higher FI conferred an odds ratio (OR) of 1.46 [95% confidence interval (CI): 1.13 to 1.87; P=0.003] for CAD, 1.62 (95% CI: 1.21 to 2.17, P=0.001) for MI, and 1.46 (95% CI: 1.24 to 1.72; P=4.89×10−6) for HF. However, FI failed to be potentially influential on AF risk (OR, 1.43; 95% CI: 0.93 to 1.66; P=0.107). Several complementary analyses also received broadly concordant results.ConclusionsWe have provided genetic evidence of a causal association between FI and the risk of CAD, MI, and HF. Further studies are warranted to clarify whether FI is causally related to AF risk.