Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study

Abstract Background The aetiology of glioma is poorly understood. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for glioma risk factors. Methods We performed an MR-PheWAS analysing 316 phenotypes, proxied by 8387 genetic variants, and summary genetic data from a GWAS of 12,488 glioma cases and 18,169 controls. Causal effects were estimated under a random-effects inverse-variance-weighted (IVW-RE) model, with robust adjusted profile score (MR-RAPS), weighted median and mode-based estimates computed to assess the robustness of findings. Odds ratios per one standard deviation increase in each phenotype were calculated for all glioma, glioblastoma (GBM) and non-GBM tumours. Results No significant associations (P < 1.58 × 10−4) were observed between phenotypes and glioma under the IVW-RE model. Suggestive associations (1.58 × 10−4 < P < 0.05) were observed between leukocyte telomere length (LTL) with all glioma (ORSD = 3.91, P = 9.24 × 10−3) and GBM (ORSD = 4.86, P = 3.23 × 10−2), but the association was primarily driven by the TERT variant rs2736100. Serum low-density lipoprotein cholesterol and plasma HbA1C showed suggestive associations with glioma (ORSD = 1.11, P = 1.39 × 10−2 and ORSD = 1.28, P = 1.73 × 10−2, respectively), both associations being reliant on single genetic variants. Conclusions Our study provides further insight into the aetiological basis of glioma for which published data have been mixed.

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Coronary artery disease, genetic risk and the metabolome in young individuals

Wellcome Open Research ◽

10.12688/wellcomeopenres.14788.1 ◽

2018 ◽

Vol 3 ◽

pp. 114 ◽

Cited By ~ 5

Author(s):

Thomas Battram ◽

Luke Hoskins ◽

David A. Hughes ◽

Johannes Kettunen ◽

Susan M. Ring ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Variants ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Artery Disease

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease. Methods: 149 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,905 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined. Results: The CAD-GRS associated with 118 of 149 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147 PCSK9, rs12149545 HERPUD1-CETP, rs17091891 LPL, rs515135 APOB, rs602633 CELSR2-PSRC1, rs651821 APOA5, rs7412 APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299 SERPINA1 and rs2519093 ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. This knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise.

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Coronary artery disease, genetic risk and the metabolome in young individuals

Wellcome Open Research ◽

10.12688/wellcomeopenres.14788.2 ◽

2019 ◽

Vol 3 ◽

pp. 114 ◽

Cited By ~ 3

Author(s):

Thomas Battram ◽

Luke Hoskins ◽

David A. Hughes ◽

Johannes Kettunen ◽

Susan M. Ring ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Genetic Variants ◽

Genetic Risk ◽

Association Studies ◽

Genetic Risk Score ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Artery Disease

Background: Genome-wide association studies have identified genetic variants associated with coronary artery disease (CAD) in adults – the leading cause of death worldwide. It often occurs later in life, but variants may impact CAD-relevant phenotypes early and throughout the life-course. Cohorts with longitudinal and genetic data on thousands of individuals are letting us explore the antecedents of this adult disease. Methods: 148 metabolites, with a focus on the lipidome, measured using nuclear magnetic resonance (1H-NMR) spectroscopy, and genotype data were available from 5,907 individuals at ages 7, 15, and 17 years from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Linear regression was used to assess the association between the metabolites and an adult-derived genetic risk score (GRS) of CAD comprising 146 variants. Individual variant-metabolite associations were also examined. Results: The CAD-GRS associated with 118 of 148 metabolites (false discovery rate [FDR] < 0.05), the strongest associations being with low-density lipoprotein (LDL) and atherogenic non-LDL subgroups. Nine of 146 variants in the GRS associated with one or more metabolites (FDR < 0.05). Seven of these are within lipid loci: rs11591147 PCSK9, rs12149545 HERPUD1-CETP, rs17091891 LPL, rs515135 APOB, rs602633 CELSR2-PSRC1, rs651821 APOA5, rs7412 APOE-APOC1. All associated with metabolites in the LDL or atherogenic non-LDL subgroups or both including aggregate cholesterol measures. The other two variants identified were rs112635299 SERPINA1 and rs2519093 ABO. Conclusions: Genetic variants that influence CAD risk in adults are associated with large perturbations in metabolite levels in individuals as young as seven. The variants identified are mostly within lipid-related loci and the metabolites they associated with are primarily linked to lipoproteins. Along with further research, this knowledge could allow for preventative measures, such as increased monitoring of at-risk individuals and perhaps treatment earlier in life, to be taken years before any symptoms of the disease arise.

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P0770IMPAIRED FASTING GLUCOSE AND CHRONIC KIDNEY DISEASE: A MENDELIAN RANDOMIZATION STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0770 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Hyunjin Noh ◽

Hyoungnae Kim ◽

Su Yeon Park ◽

Dohui Hwang ◽

Kyoungin Choi

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Genetic Variants ◽

Mendelian Randomization ◽

Fasting Glucose ◽

Association Studies ◽

Genetic Risk Score ◽

Genome Wide Association Studies ◽

Standard Deviation Increase ◽

Inverse Variance

Abstract Background and Aims Diabetes mellitus is a risk factor of chronic kidney disease (CKD); however, the relationship between fasting glucose and CKD remains controversial in non-diabetic population. Method This study included 6,354 participants without diabetes and CKD from the KoreanGenome Epidemiology Study. The genetic risk score (GRS9) was calculated using nine genetic variants associated with fasting glucose in previous genome wide association studies. Incident CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or proteinuria (≥1+). The causal relationship between fasting glucose and CKD was evaluated using Mendelian randomization (MR) approach. Results The GRS9 was strongly associated with fasting glucose (β, 1.01; P < 0.001). During a median follow-up of 11.6 years, 531 (8.4%) CKD events occurred. After adjusting for confounding factors, fasting glucose was not associated with incident CKD (odds ratio [OR], 0.991; 95% confidence interval [CI], 0.980–1.003; P =0.139). In the MR analysis, GRS9 was not associated with CKD development (OR per 1 standard deviation increase, 1.179; 95% CI, 0.819–1.696; P = 0.376). Further evaluation with various other MR methods using inverse-variance weighted, MR-Egger, and weighted median methods for multiple genetic variants and strict CKD criteria (decrease in the eGFR of ≥ 30% to a value of < 60 mL/min/1.73m2) found no significant relationship between GRS9 and incident CKD. Conclusion Impaired fasting glucose was not causally associated with CKD development in nondiabetic population.

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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

10.1101/2020.03.19.20031138 ◽

2020 ◽

Author(s):

Caroline J. Bull ◽

Joshua A. Bell ◽

Neil Murphy ◽

Eleanor Sanderson ◽

George Davey Smith ◽

...

Keyword(s):

Colorectal Cancer ◽

Mendelian Randomization ◽

Association Studies ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Lipoprotein Subclass ◽

Site Specific ◽

Metabolic Alterations ◽

Inverse Variance

AbstractImportanceEvidence on adiposity altering colorectal cancer (CRC) risk differently among men and women, and on metabolic alterations mediating effects of adiposity on CRC, is unclear.ObjectiveTo examine sex- and site-specific associations of adiposity with CRC risk, and whether adiposity-associated metabolites explain associations of adiposity with CRC.DesignTwo-sample Mendelian randomization (MR) study.SettingGenetic variants from expanded genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N=806,810), and 123 metabolites (mostly lipoprotein subclass-specific lipids) from targeted nuclear magnetic resonance metabolomics (N=24,925), were used as instruments. Sex-combined and sex-specific MR was conducted for BMI and WHR with CRC risk; sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes.Participants58,221 cases and 67,694 controls (Genetics and Epidemiology of Colorectal Cancer Consortium; Colorectal Cancer Transdisciplinary Study; Colon Cancer Family Registry).Main outcome measuresIncident CRC (overall and site-specific).ResultsAmong men, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95%-confidence interval (CI)=1.08, 1.38) times higher CRC odds (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95%-CI=0.97, 1.22) times higher CRC odds. Higher WHR was more strongly associated with CRC risk among women (IVW-OR=1.25, 95%-CI=1.08, 1.43 per 0.07-ratio) than men (IVW-OR=1.05, 95%-CI=0.81, 1.36 per 0.07-ratio). BMI or WHR was associated with 104 metabolites (false-discovery-rate-corrected P≤0.05) including low-density lipoprotein (LDL) cholesterol, but these metabolites were generally unassociated with CRC in directions consistent with mediation of adiposity-CRC relations. In multivariable MR, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes – e.g. the univariable IVW-OR of BMI for CRC was 1.12 (95%-CI=1.00, 1.26), and 1.11 (95%-CI=0.99, 1.26) adjusting for LDL lipids.Conclusions and relevanceOur results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women.Adiposity was associated with numerous metabolic alterations, but none of these alterations explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify mechanistic pathways.

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Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

BMC Medicine ◽

10.1186/s12916-020-01855-9 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Caroline J. Bull ◽

Joshua A. Bell ◽

Neil Murphy ◽

Eleanor Sanderson ◽

George Davey Smith ◽

...

Keyword(s):

Colorectal Cancer ◽

Mendelian Randomization ◽

Association Studies ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Metabolic Alterations ◽

Genome Wide ◽

Inverse Variance ◽

Colon Cancer Family Registry

Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

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Genetic evidence for a causative effect of airflow obstruction on left ventricular filling: a Mendelian randomisation study

Respiratory Research ◽

10.1186/s12931-021-01795-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lars Harbaum ◽

Jan K. Hennigs ◽

Marcel Simon ◽

Tim Oqueka ◽

Henrik Watz ◽

...

Keyword(s):

General Population ◽

Genetic Variants ◽

Airflow Obstruction ◽

Left Ventricular ◽

Sensitivity Analyses ◽

Weighted Regression ◽

Mendelian Randomisation ◽

Effect Estimate ◽

Genome Wide Association Studies ◽

Inverse Variance

Abstract Background Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. Methods We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. Results We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Conclusion Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

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LPA and APOE are associated with statin selection in the UK Biobank

10.1101/2020.08.28.272765 ◽

2020 ◽

Author(s):

Adam Lavertu ◽

Gregory McInnes ◽

Yosuke Tanigawa ◽

Russ B Altman ◽

Manuel A. Rivas

Keyword(s):

Statin Therapy ◽

High Intensity ◽

Drug Response ◽

Association Studies ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Treatment Decisions ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

The Uk

AbstractGenetics plays a key role in drug response, affecting efficacy and toxicity. Pharmacogenomics aims to understand how genetic variation influences drug response and develop clinical guidelines to aid clinicians in personalized treatment decisions informed by genetics. Although pharmacogenomics has not been broadly adopted into clinical practice, genetics influences treatment decisions regardless. Physicians adjust patient care based on observed response to medication, which may occur as a result of genetic variants harbored by the patient. Here we seek to understand the genetics of drug selection in statin therapy, a class of drugs widely used for high cholesterol treatment. Genetics are known to play an important role in statin efficacy and toxicity, leading to significant changes in patient outcome. We performed genome-wide association studies (GWAS) on statin selection among 59,198 participants in the UK Biobank and found that variants known to influence statin efficacy are significantly associated with statin selection. Specifically, we find that carriers of variants in APOE and LPA that are known to decrease efficacy of treatment are more likely to be on atorvastatin, a stronger statin. Additionally, carriers of the APOE and LPA variants are more likely to be on a higher intensity dose (a dose that reduces low-density lipoprotein cholesterol by greater than 40%) of atorvastatin than non-carriers (APOE: p(high intensity) = 0.16, OR = 1.7, P = 1.64 × 10−4, LPA: p(high intensity) = 0.17, OR = 1.4, P = 1.14 × 10−2). These findings represent the largest genetic association study of statin selection and statin dose association to date and provide evidence for the role of LPA and APOE in statin response, furthering the possibility of personalized statin therapy.

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Lipid associated polygenic enrichment in Alzheimer’s disease

10.1101/383844 ◽

2018 ◽

Author(s):

Iris J. Broce ◽

Chin Hong Tan ◽

Chun Chieh Fan ◽

Aree Witoelar ◽

Natalie Wen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Plasma Lipids ◽

Association Studies ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Pleiotropy ◽

Common Genetic Variants

ABSTRACTCardiovascular (CV) and lifestyle associated risk factors (RFs) are increasingly recognized as important for Alzheimer’s disease (AD) pathogenesis. Beyond the ∊4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV associated genes also increase risk for AD (genetic pleiotropy). Using large genome-wide association studies (GWASs) (total n > 500,000 cases and controls) and validated tools to quantify genetic pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 57 SNPs on 19 different chromosomes that were jointly associated with AD and CV outcomes including APOA4, ABCA1, ABCG5, LIPG, and MTCH2/SPI1. We found that common genetic variants influencing AD are associated with multiple CV RFs, at times with a different directionality of effect. Expression of these AD/CV pleiotropic genes was enriched for lipid metabolism processes, over-represented within astrocytes and vascular structures, highly co-expressed, and differentially altered within AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid associated RFs. Rather than a single causal link between genetic loci, RF and the outcome, we found that common genetic variants influencing AD are associated with multiple CV RFs. Our collective findings suggest that a network of genes involved in lipid biology also influence Alzheimer’s risk.

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Investigating genetically mimicked effects of statins via HMGCR inhibition on immune-related diseases in men and women using Mendelian randomization

Scientific Reports ◽

10.1038/s41598-021-02981-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Guoyi Yang ◽

C. Mary Schooling

Keyword(s):

Lupus Erythematosus ◽

Multiple Testing ◽

Mendelian Randomization ◽

Association Studies ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Allergic Diseases ◽

Genome Wide Association Studies ◽

East Asians ◽

Genome Wide

AbstractStatins have been suggested as a potential treatment for immune-related diseases. Conversely, statins might trigger auto-immune conditions. To clarify the role of statins in allergic diseases and auto-immune diseases, we conducted a Mendelian randomization (MR) study. Using established genetic instruments to mimic statins via 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibition, we assessed the effects of statins on asthma, eczema, allergic rhinitis, rheumatoid arthritis (RA), psoriasis, type 1 diabetes, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Crohn’s disease and ulcerative colitis in the largest available genome wide association studies (GWAS). Genetically mimicked effects of statins via HMGCR inhibition were not associated with any immune-related diseases in either study after correcting for multiple testing; however, they were positively associated with the risk of asthma in East Asians (odds ratio (OR) 2.05 per standard deviation (SD) decrease in low-density lipoprotein cholesterol (LDL-C), 95% confidence interval (CI) 1.20 to 3.52, p value 0.009). These associations did not differ by sex and were robust to sensitivity analysis. These findings suggested that genetically mimicked effects of statins via HMGCR inhibition have little effect on allergic diseases or auto-immune diseases. However, we cannot exclude the possibility that genetically mimicked effects of statins via HMGCR inhibition might increase the risk of asthma in East Asians.

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The association between depression and metabolic syndrome and its components: a bidirectional two-sample Mendelian randomization study

Translational Psychiatry ◽

10.1038/s41398-021-01759-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Min Zhang ◽

Jing Chen ◽

Zhiqun Yin ◽

Lanbing Wang ◽

Lihua Peng

Keyword(s):

Metabolic Syndrome ◽

Waist Circumference ◽

Mendelian Randomization ◽

Association Studies ◽

Fasting Blood Glucose ◽

Density Lipoprotein ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Level Data ◽

Inverse Variance

AbstractObservational studies suggested a bidirectional correlation between depression and metabolic syndrome (MetS) and its components. However, the causal associations between them remained unclear. We aimed to investigate whether genetically predicted depression is related to the risk of MetS and its components, and vice versa. We performed a bidirectional two-sample Mendelian randomization (MR) study using summary-level data from the most comprehensive genome-wide association studies (GWAS) of depression (n = 2,113,907), MetS (n = 291,107), waist circumference (n = 462,166), hypertension (n = 463,010) fasting blood glucose (FBG, n = 281,416), triglycerides (n = 441,016), high-density lipoprotein cholesterol (HDL-C, n = 403,943). The random-effects inverse-variance weighted (IVW) method was applied as the primary method. The results identified that genetically predicted depression was significantly positive associated with risk of MetS (OR: 1.224, 95% CI: 1.091–1.374, p = 5.58 × 10−4), waist circumference (OR: 1.083, 95% CI: 1.027–1.143, p = 0.003), hypertension (OR: 1.028, 95% CI: 1.016–1.039, p = 1.34 × 10−6) and triglycerides (OR: 1.111, 95% CI: 1.060–1.163, p = 9.35 × 10−6) while negative associated with HDL-C (OR: 0.932, 95% CI: 0.885–0.981, p = 0.007) but not FBG (OR: 1.010, 95% CI: 0.986–1.034, p = 1.34). No causal relationships were identified for MetS and its components on depression risk. The present MR analysis strength the evidence that depression is a risk factor for MetS and its components (waist circumference, hypertension, FBG, triglycerides, and HDL-C). Early diagnosis and prevention of depression are crucial in the management of MetS and its components.

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