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BACKGROUND AND OBJECTIVES: Anxiety and depression have implications for ischemic stroke recovery. This study explored the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke using Mendelian randomization (MR) approach. METHODS: Independent genetic variants associated with anxiety and depression at genome-wide significance level (p < 5 × 10-8) were obtained from large-scale genome-wide association studies (Nmax = 1,306,354). Genetic results of poststroke outcome were obtained from Genetics of Ischemic Stroke Functional Outcome meta-analysis (N = 6,021). Three months after ischemic stroke event, the functional outcome was appraised with the modified Rankin Scale (mRS) score, and a mRS >2 was defined as worse functional outcome. Odds ratios (ORs) and 95% CIs are reported for the association of genetically predicted anxiety and depression with functional outcome after ischemic stroke. The inverse-variance weighted method was adopted to pool estimates. Alternative MR methods such as the weighted median and MR using the Robust Adjusted Profile Score were used as sensitivity analyses. The intercept of MR-Egger regression was also adopted to assess pleiotropy. The heterogeneity among variants was assessed by I2 and Q statistics. RESULTS: Genetic liability to depression was associated with worse functional outcome after stroke (mRS 3-6, OR 2.30; 95% CI 1.18-4.49, p = 0.015). Sensitivity analyses produced consistent results. The bidirectional MR analysis indicates that poststroke outcome did not influence liability to depression (OR 1.01, 95% CI 0.99-1.03; p = 0.436). By comparison, genetic liability to anxiety was not related with poststroke outcome (OR 1.03; 95% CI 0.71-1.50; p = 0.869). Analyses in models without adjustment for stroke severity also indicated that genetic liability to depression was related with poor functional outcome after ischemic stroke (OR 2.54; 95% CI 1.41-4.58; p = 0.002). No evidence of heterogeneity or directional pleiotropy was observed (p > 0.05). DISCUSSION: Our MR study provides evidence to support detrimental effects of depression on ischemic stroke functional outcome. Future studies are warranted to explore whether clinical intervention on depression can ameliorate functional outcome after ischemic stroke.
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Ansiedad , Depresión , Estudio de Asociación del Genoma Completo , Accidente Cerebrovascular Isquémico , Análisis de la Aleatorización Mendeliana , Humanos , Accidente Cerebrovascular Isquémico/genética , Accidente Cerebrovascular Isquémico/psicología , Accidente Cerebrovascular Isquémico/complicaciones , Depresión/genética , Depresión/etiología , Depresión/epidemiología , Ansiedad/genética , Ansiedad/etiología , Recuperación de la FunciónRESUMEN
BACKGROUND: Circulating plasma proteins are clinically useful biomarkers for stroke risk. We examined the causal links between plasma proteins and stroke risk in individuals of South Asian ancestry. METHODS AND RESULTS: We applied proteome-wide Mendelian randomization and colocalization approaches to understand causality of 2922 plasma proteins on stroke risk in individuals of South Asian ancestry. We obtained genetic instruments (proxies) for plasma proteins from the UK Biobank (N=920). Genome-wide association studies summary data for strokes (N≤11 312) were sourced from GIGASTROKE consortium. Our primary approach involved the Wald ratio or inverse-variance-weighted methods, with statistical significance set at false discovery rate <0.1. Additionally, a Bayesian colocalization approach assessed shared causal variants among proteome, transcriptome, and stroke phenotypes to minimize bias from linkage disequilibrium. We found evidence of a potential causal effect of plasma GP6 (glycoprotein VI) levels on cardioembolic stroke (odds ratio [OR]Wald ratio=2.53 [95% CI, 1.59-4.03]; P=9.2×10-5, false discovery rate=0.059). Generalized Mendelian randomization accounting for correlated single nucleotide polymorphisms (SNPs), with the P value threshold at P<5×10-8 and clumped at r2=0.3, showed consistent direction of effect of GP6 on cardioembolic stroke (ORgeneralized inverse-variance-weighted=2.21 [95% CI, 1.46-3.33]; P=1.6×10-4). Colocalization analysis indicated that plasma GP6 levels colocalize with cardioembolic stroke (posterior probability=91.4%). Multitrait colocalization combining transcriptome, proteome, and cardioembolic stroke showed moderate to strong evidence that these 2 traits colocalize with GP6 expression in the coronary artery and brain tissues (multitrait posterior probability>50%). The potential causal effect of GP6 on cardioembolic stroke was not significant in European populations (ORinverse-variance-weighted=1.08 [95% CI, 0.93-1.26]; P=0.29). CONCLUSIONS: Our joint Mendelian randomization and colocalization analyses suggest that genetically predicted GP6 is potentially causally associated with cardioembolic stroke risk in individuals of South Asian ancestry. As genetic data on individuals of South Asian ancestry increase, future Mendelian randomization studies with larger sample size for plasma GP6 levels should be implemented to further validate our findings. Additionally, clinical studies will be necessary to verify GP6 as a therapeutic target for cardioembolic stroke in South Asians.
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Pueblo Asiatico , Teorema de Bayes , Accidente Cerebrovascular Embólico , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Glicoproteínas de Membrana Plaquetaria , Polimorfismo de Nucleótido Simple , Humanos , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/epidemiología , Accidente Cerebrovascular Embólico/sangre , Pueblo Asiatico/genética , Glicoproteínas de Membrana Plaquetaria/genética , Glicoproteínas de Membrana Plaquetaria/metabolismo , Femenino , Masculino , Factores de Riesgo , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Biomarcadores/sangre , Anciano , Medición de Riesgo/métodosRESUMEN
Plasma low-density lipoprotein (LDL)-cholesterol is positively associated with coronary artery disease risk while biliary cholesterol promotes gallstone formation. Different plasma LDL-cholesterol lowering pathways may have distinct effects on biliary cholesterol and thereby gallstone disease risk. We conducted a Mendelian randomization (MR) study using data from the UK Biobank (30,547 gallstone disease cases/336,742 controls), FinnGen (34,461 cases/301,383 controls) and Biobank Japan (9,305 cases/168,253 controls). We first performed drug-target MR analyses substantiated by colocalization to investigate the effects of plasma LDL-cholesterol lowering therapies on gallstone disease risk. We then performed clustered MR analyses and pathway analyses to identify distinct mechanisms underlying the association of plasma LDL-cholesterol with gallstone disease risk. For a 1-standard deviation reduction in plasma LDL-cholesterol, genetic mimics of statins were associated with lower gallstone disease risk (odds ratio 0.72 [95% confidence interval 0.62, 0.83]), but genetic mimics of PCSK9 inhibitors and targeting apolipoprotein B were associated with higher risk (1.11 [1.03, 1.19] and 1.23 [1.13, 1.35]). The association for statins was supported by colocalization (posterior probability 98.7%). Clustered MR analyses identified variant clusters showing opposing associations of plasma LDL-cholesterol with gallstone disease risk, with some evidence for ancestry-and sex-specific associations. Among variants lowering plasma LDL-cholesterol, those associated with lower gallstone disease risk were mapped to glycosphingolipid biosynthesis pathway, while those associated with higher risk were mapped to pathways relating to plasma lipoprotein assembly, remodelling, and clearance and ATP-binding cassette transporters. This MR study provides genetic evidence that different plasma LDL-cholesterol lowering pathways have opposing effects on gallstone disease risk.
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Purpose: To investigate the causal effect of elevated blood pressure on primary open-angle glaucoma (POAG) and POAG endophenotypes. Methods: Two-sample Mendelian randomization (MR) was performed to investigate the causal effect of elevated systolic blood pressure (SBP) (N = 757,601) and diastolic blood pressure (DBP) (N = 757,601) on intraocular pressure (IOP) (N = 139,555), macular retinal nerve fiber layer (mRNFL) thickness (N = 33,129), ganglion cell complex (GCC) thickness (N = 33,129), vertical cup-to-disc ratio (VCDR) (N = 111,724), and POAG liability (Ncases = 16,677, Ncontrols = 199,580). The primary analysis was conducted using the inverse-variance weighted approach. Sensitivity analyses were performed to investigate robustness to horizontal pleiotropy, winner's curse, and collider bias. Multivariable MR was performed to investigate whether any effect of blood pressure on retinal ganglion cell degeneration was mediated through increased IOP. Results: Increased genetically predicted SBP and DBP associated with an increase in IOP (0.17 mm Hg [95% CI = 0.11 to 0.24] per 10 mm Hg higher SBP, P = 5.18 × 10-7, and 0.17 mm Hg [95% CI = 0.05 to 0.28 mm Hg] per 10 mm Hg higher DBP, P = 0.004). Increased genetically predicted SBP associated with a thinner GCC (0.04 µm [95% CI = -0.07 to -0.01 µm], P = 0.018) and a thinner mRNFL (0.04 µm [95% CI = -0.07 to -0.01 µm], P = 0.004), an effect that arises independently of IOP according to our mediation analysis. Neither SBP nor DBP associated with VCDR or POAG liability. Conclusions: These findings support a causal effect of elevated blood pressure on retinal ganglion cell degeneration that does not require intermediary changes in IOP. Targeted blood pressure control may help preserve vision by lowering IOP and, independently, by preventing retinal ganglion cell degeneration, including in individuals with a normal IOP.
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Presión Sanguínea , Glaucoma de Ángulo Abierto , Presión Intraocular , Análisis de la Aleatorización Mendeliana , Células Ganglionares de la Retina , Presión Intraocular/fisiología , Células Ganglionares de la Retina/patología , Humanos , Glaucoma de Ángulo Abierto/genética , Glaucoma de Ángulo Abierto/fisiopatología , Presión Sanguínea/fisiología , Fibras Nerviosas/patología , Degeneración Retiniana/genética , Degeneración Retiniana/fisiopatología , Masculino , Polimorfismo de Nucleótido Simple , FemeninoRESUMEN
BACKGROUND: Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. METHODS AND RESULTS: We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. CONCLUSIONS: We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.
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Índice de Masa Corporal , Grosor Intima-Media Carotídeo , Hipertensión , Menarquia , Análisis de la Aleatorización Mendeliana , Humanos , Femenino , Menarquia/genética , Hipertensión/genética , Hipertensión/epidemiología , Hipertensión/fisiopatología , Factores de Edad , Masculino , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Aterosclerosis/genética , Aterosclerosis/epidemiología , Factores Sexuales , Factores de Riesgo , Adolescente , Presión Sanguínea/genética , Medición de Riesgo , Enfermedades Asintomáticas , Factores de Riesgo CardiometabólicoRESUMEN
BACKGROUND: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. AIMS: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. METHODS: We conducted a sex-specific two-sample Mendelian randomization study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e. aSAH and unruptured IA combined) as outcomes. RESULTS: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (p-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (p-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (p-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. CONCLUSIONS: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.
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Background: The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. Aims: The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. Methods: We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. Results: We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Conclusions: Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.
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Estudio de Asociación del Genoma Completo , Aneurisma Intracraneal , Análisis de la Aleatorización Mendeliana , Hemorragia Subaracnoidea , Humanos , Hemorragia Subaracnoidea/epidemiología , Hemorragia Subaracnoidea/genética , Hemorragia Subaracnoidea/sangre , Femenino , Masculino , Aneurisma Intracraneal/genética , Aneurisma Intracraneal/epidemiología , Factores Sexuales , Medición de Riesgo , Factores de Riesgo , Incidencia , Predisposición Genética a la Enfermedad , Disparidades en el Estado de Salud , PrevalenciaRESUMEN
Aims: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods and results: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses. Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
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Receptor del Péptido 1 Similar al Glucagón , Análisis de la Aleatorización Mendeliana , Suicidio , Humanos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/genética , Hipoglucemiantes/uso terapéutico , Hipoglucemiantes/efectos adversos , Medición de Riesgo , Factores de Riesgo , Suicidio/estadística & datos numéricosRESUMEN
BACKGROUND AND OBJECTIVES: Obesity is hypothesized to induce a hypercoagulable state that increases stroke risk. The molecular mechanisms underlying this association are largely uncharacterized. We aimed to apply mendelian randomization to identify whether the association of genetically proxied body mass index (BMI) with cardioembolic stroke risk is mediated by changes in levels of circulating coagulation factors. METHODS: Genetic proxies for BMI and levels of circulating coagulation factors were obtained, respectively, from the Genetic Investigation of ANthropometric Traits consortium (n = 694,649) and deCODE cohort (n = 35,559). Genetic associations with cardioembolic stroke risk were obtained from the GIGASTROKE consortium (10,804 cases and 1,234,804 controls). We performed a two-sample mendelian randomization analysis testing the association of genetically proxied BMI with cardioembolic stroke risk, genetically proxied BMI with levels of coagulation factors, and genetically proxied levels of coagulation factors with cardioembolic stroke risk. These estimates were carried forward to mediation and sensitivity analyses. RESULTS: A 1-SD increase in genetically proxied BMI associated with increased cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD of BMI 1.20, 95% CI 1.08-1.33, p = 8.65 × 10-4) with similar findings in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Genetically proxied BMI was further associated with increased levels of Factor VII, Factor Xa, Factor XI, and Protein S (all p < 5.9 × 10-6). Of these factors, genetically proxied levels of Factor XI were associated with cardioembolic stroke risk (OR of cardioembolic stroke per 1-SD increase in Factor XI levels 1.32, 1.19-1.46, p = 6.18 × 10-8). The mediated effect of genetically proxied BMI through Factor XI accounted for 26% (6%-49%) of the total effect of BMI on cardioembolic stroke. DISCUSSION: Human genetic data support increased levels of Factor XI as a mechanistic explanation for how obesity increases cardioembolic stroke risk. The clinical relevance of this association warrants further investigation within ongoing clinical trials of Factor XI inhibition.
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Índice de Masa Corporal , Análisis de la Aleatorización Mendeliana , Obesidad , Trombofilia , Humanos , Obesidad/genética , Obesidad/complicaciones , Obesidad/sangre , Obesidad/epidemiología , Trombofilia/genética , Trombofilia/sangre , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/sangre , Femenino , Factores de Coagulación Sanguínea/genética , Masculino , Factores de Riesgo , Accidente Cerebrovascular Embólico/genética , Accidente Cerebrovascular Embólico/epidemiologíaRESUMEN
Low concentrations of circulating 25-hydroxy-vitamin D are observationally associated with an increased risk of subclinical atherosclerosis and cardiovascular disease. However, randomized controlled trials have not reported the beneficial effects of vitamin D supplementation on atherosclerotic cardiovascular disease (ASCVD) outcomes. Whether genetically predicted vitamin D status confers protection against the development of carotid artery plaque, a powerful predictor of subclinical atherosclerosis, remains unknown. We conducted a two-sample Mendelian randomization (MR) study to explore the association of genetically predicted vitamin D status and deficiency with the risk of developing carotid artery plaque. We leveraged three genome-wide association studies (GWAS) of vitamin D status and one GWAS of vitamin D deficiency. We used the inverse-variance weighted (IVW) approach as our main method, and MR-Egger, weighted-median, and radialMR as MR sensitivity analyses. We also conducted sensitivity analyses using biologically plausible genetic instruments located within genes encoding for vitamin D metabolism (GC, CYP2R1, DHCR7, CYP24A1). We did not find significant associations between genetically predicted vitamin D status (Odds ratio (OR) = 0.99, P = 0.91) and deficiency (OR = 1.00, P = 0.97) with the risk of carotid artery plaque. We additionally explored the potential causal effect of vitamin D status on coronary artery calcification (CAC) and carotid intima-media thickness (cIMT), two additional markers of subclinical atherosclerosis, and we did not find any significant association (ßCAC = - 0.14, P = 0.23; ßcIMT = 0.005, P = 0.19). These findings did not support the causal effects of vitamin D status and deficiency on the risk of developing subclinical atherosclerosis.
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Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Placa Aterosclerótica , Deficiencia de Vitamina D , Vitamina D , Humanos , Vitamina D/sangre , Vitamina D/análogos & derivados , Deficiencia de Vitamina D/genética , Deficiencia de Vitamina D/complicaciones , Placa Aterosclerótica/genética , Enfermedades de las Arterias Carótidas/genética , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Predisposición Genética a la Enfermedad , Femenino , Masculino , Arterias Carótidas/patología , Arterias Carótidas/diagnóstico por imagenAsunto(s)
Población Negra , Accidente Cerebrovascular Isquémico , Análisis de la Aleatorización Mendeliana , Población Blanca , Humanos , Accidente Cerebrovascular Isquémico/genética , Población Negra/genética , Población Blanca/genética , Hipolipemiantes/uso terapéutico , Factores de Riesgo , Polimorfismo de Nucleótido SimpleRESUMEN
Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.
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BACKGROUND: Mendelian randomisation (MR) is the use of genetic variants as instrumental variables. Mode-based estimators (MBE) are one of the most popular types of estimators used in univariable-MR studies and is often used as a sensitivity analysis for pleiotropy. However, because there are no plurality valid regression estimators, modal estimators for multivariable-MR have been under-explored. METHODS: We use the residual framework for multivariable-MR to introduce two multivariable modal estimators: multivariable-MBE, which uses IVW to create residuals fed into a traditional plurality valid estimator, and an estimator which instead has the residuals fed into the contamination mixture method (CM), multivariable-CM. We then use Monte-Carlo simulations to explore the performance of these estimators when compared to existing ones and re-analyse the data used by Grant and Burgess (2021) looking at the causal effect of intelligence, education, and household income on Alzheimer's disease as an applied example. RESULTS: In our simulation, we found that multivariable-MBE was generally too variable to be much use. Multivariable-CM produced more precise estimates on the other hand. Multivariable-CM performed better than MR-Egger in almost all settings, and Weighted Median under balanced pleiotropy. However, it underperformed Weighted Median when there was a moderate amount of directional pleiotropy. Our re-analysis supported the conclusion of Grant and Burgess (2021), that intelligence had a protective effect on Alzheimer's disease, while education, and household income do not have a causal effect. CONCLUSIONS: Here we introduced two, non-regression-based, plurality valid estimators for multivariable MR. Of these, "multivariable-CM" which uses IVW to create residuals fed into a contamination-mixture model, performed the best. This estimator uses a plurality of variants valid assumption, and appears to provide precise and unbiased estimates in the presence of balanced pleiotropy and small amounts of directional pleiotropy.
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Análisis de la Aleatorización Mendeliana , Análisis de la Aleatorización Mendeliana/métodos , Humanos , Enfermedad de Alzheimer/genética , Método de Montecarlo , Análisis Multivariante , Simulación por Computador , Variación Genética , Programas InformáticosRESUMEN
BACKGROUND: The genetic and nongenetic causes of intracerebral hemorrhage (ICH) remain obscure. The present study aimed to uncover the genetic and modifiable risk factors for ICH. METHODS: We meta-analyzed genome-wide association study data from 3 European biobanks, involving 7605 ICH cases and 711â 818 noncases, to identify the genomic loci linked to ICH. To uncover the potential causal associations of cardiometabolic and lifestyle factors with ICH, we performed Mendelian randomization analyses using genetic instruments identified in previous genome-wide association studies of the exposures and ICH data from the present genome-wide association study meta-analysis. We performed multivariable Mendelian randomization analyses to examine the independent associations of the identified risk factors with ICH and evaluate potential mediating pathways. RESULTS: We identified 1 ICH risk locus, located at the APOE genomic region. The lead variant in this locus was rs429358 (chr19:45411941), which was associated with an odds ratio of ICH of 1.17 (95% CI, 1.11-1.20; P=6.01×10-11) per C allele. Genetically predicted higher levels of body mass index, visceral adiposity, diastolic blood pressure, systolic blood pressure, and lifetime smoking index, as well as genetic liability to type 2 diabetes, were associated with higher odds of ICH after multiple testing corrections. Additionally, a genetic increase in waist-to-hip ratio and liability to smoking initiation were consistently associated with ICH, albeit at the nominal significance level (P<0.05). Multivariable Mendelian randomization analysis showed that the association between body mass index and ICH was attenuated on adjustment for type 2 diabetes and further that type 2 diabetes may be a mediator of the body mass index-ICH relationship. CONCLUSIONS: Our findings indicate that the APOE locus contributes to ICH genetic susceptibility in European populations. Excess adiposity, elevated blood pressure, type 2 diabetes, and smoking were identified as the chief modifiable cardiometabolic and lifestyle factors for ICH.
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Hemorragia Cerebral , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Humanos , Hemorragia Cerebral/genética , Hemorragia Cerebral/epidemiología , Factores de Riesgo , Masculino , Femenino , Polimorfismo de Nucleótido Simple , Apolipoproteínas E/genética , Persona de Mediana Edad , Predisposición Genética a la Enfermedad/genética , Anciano , Índice de Masa Corporal , Fumar/genética , Fumar/epidemiologíaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.
Asunto(s)
Índice de Masa Corporal , Neoplasias Colorrectales , Análisis de la Aleatorización Mendeliana , Obesidad , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/epidemiología , Factores de Riesgo , Obesidad/genética , Obesidad/epidemiología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Consumo de Bebidas Alcohólicas/epidemiologíaRESUMEN
Background: Adverse pregnancy outcomes are predictive for future cardiovascular disease risk, but it is unclear whether they play a causal role. We conducted a Mendelian randomization study with males as a negative control population to estimate the associations between genetic liability to adverse pregnancy outcomes and risk of coronary artery disease. Methods: We extracted uncorrelated (R2<0.01) single-nucleotide polymorphisms strongly associated (p-value<5e-8) with miscarriage, gestational diabetes, hypertensive disorders of pregnancy, preeclampsia, placental abruption, poor fetal growth and preterm birth from relevant genome-wide association studies. Genetic associations with risk of coronary artery disease were extracted separately for females and males. The main analysis was the inverse-variance weighted analysis, while MR Egger, weighted median and weighted mode regression, bidirectional analyses, and the negative control population with males were sensitivity analyses to evaluate bias due to genetic pleiotropy. Results: The number of cases for the adverse pregnancy outcomes ranged from 691 (182,824 controls) for placental abruption to 49,996 (174,109 controls) for miscarriage, and there were 22,997 (310,499 controls) and 54,083 (240,453 controls) cases of coronary artery disease for females and males, respectively. We observed an association between genetic liability to hypertensive disorders of pregnancy and preeclampsia, and to some extent gestational diabetes, poor fetal growth and preterm birth, with an increased risk of coronary artery disease among females, which was supported by the MR Egger, weighted median and weighted mode regressions. However, in the negative control population of males, we observed largely the same associations as for females. Conclusions: The associations between adverse pregnancy outcomes and coronary artery disease risk were likely driven by confounding (e.g., shared genetic liability). Thus, our study does not support the hypothesis that adverse pregnancy outcomes are causal risk factors for cardiovascular diseases.