Causal Effect of the Triglyceride-Glucose Index and the Joint Exposure of Higher Glucose and Triglyceride With Extensive Cardio-Cerebrovascular Metabolic Outcomes in the UK Biobank: A Mendelian Randomization Study

Background: The causal evidence of the triglyceride–glucose (TyG) index, as well as the joint exposure of higher glucose and triglyceride on the risk of cardio-cerebrovascular diseases (CVD), was lacking.Methods: A comprehensive factorial Mendelian randomization (MR) was performed in the UK Biobank cohort involving 273,368 individuals with European ancestry to assess and quantify these effects. The factorial MR, MR-PRESSO, MR-Egger, meta-regression, sensitivity analysis, positive control, and external verification were utilized. Outcomes include major outcomes [overall CVD, ischemic heart diseases (IHD), and cerebrovascular diseases (CED)] and minor outcomes [angina pectoris (AP), acute myocardial infarction (AMI), chronic IHD (CIHD), heart failure (HF), hemorrhagic stroke (HS), and ischemic stroke (IS)].Results: The TyG index significantly increased the risk of overall CVD [OR (95% CI): 1.20 (1.14–1.25)], IHD [OR (95% CI): 1.22 (1.15–1.29)], CED [OR (95% CI): 1.14 (1.05–1.23)], AP [OR (95% CI): 1.29 (1.20–1.39)], AMI [OR (95% CI): 1.27 (1.16–1.39)], CIHD [OR (95% CI): 1.21 (1.13–1.29)], and IS [OR (95% CI): 1.22 (1.06–1.40)]. Joint exposure to genetically higher GLU and TG was significantly associated with a higher risk of overall CVD [OR (95% CI): 1.17 (1.12–1.23)] and IHD [OR (95% CI): 1.22 (1.16–1.29)], but not with CED. The effect of GLU and TG was independent of each other genetically and presented dose–response effects in bivariate meta-regression analysis.Conclusions: Lifelong genetic exposure to higher GLU and TG was jointly associated with higher cardiac metabolic risk while the TyG index additionally associated with several cerebrovascular diseases. The TyG index could serve as a more sensitive pre-diagnostic indicator for CVD while the joint GLU and TG could offer a quantitative risk for cardiac metabolic outcomes.

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Causal Association Between Atopic Dermatitis and Inflammatory Bowel Disease: A 2-Sample Bidirectional Mendelian Randomization Study

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab329 ◽

2021 ◽

Author(s):

Christa Meisinger ◽

Dennis Freuer

Keyword(s):

Inflammatory Bowel Disease ◽

Atopic Dermatitis ◽

Bowel Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

The Other ◽

Uk Biobank ◽

Inflammatory Bowel ◽

The Uk

Abstract Background Observational studies postulated an association between atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, it remains unclear whether this relationship is causal. Methods To determine whether AD is causally related to IBD and vice versa, a 2-sample Mendelian randomization study was conducted. Independent genetic instruments from the largest available genome-wide association study for AD (EAGLE eczema consortium without the 23andMe study including 10,788 cases and 30,047 controls) were used to investigate the association with IBD in the UK Biobank study (7045 cases, 456,327 controls) and a second European IBD sample (12,882 cases, 21,770 controls). Results Atopic dermatitis was strongly associated with higher risk of IBD as a whole (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.035; 1.183; P = .003) in the UK Biobank study. The positive association was not significant in the other IBD study (OR, 1.114; 95% CI, 0.956; 1.298), but in meta-analyses of results from the 2 studies, the strong association could be confirmed (OR, 1.11; 95% CI, 1.04; 1.18). When evaluating the causal relationship in the other direction, IBD as a whole did not show an association with AD. Subtype analyses revealed that AD was suggestively associated with ulcerative colitis (UC; OR, 1.149; 95% CI, 1.018; 1.297) but not Crohn’s disease (CD). However, there was a suggestive association between CD and AD (OR, 1.034; 95% CI, 1.004; 1.064) but not UC and AD. Conclusions This study supports a causal effect between AD and IBD—but not between IBD and AD. There seems to be considerable differences between UC and CD regarding their specific associations with AD. These findings have implications for the management of IBD and AD in clinical practice.

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Does Obesity Cause Thyroid Cancer? A Mendelian Randomization Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa250 ◽

2020 ◽

Vol 105 (7) ◽

pp. e2398-e2407

Author(s):

Jonathan Mark Fussey ◽

Robin N Beaumont ◽

Andrew R Wood ◽

Bijay Vaidya ◽

Joel Smith ◽

...

Keyword(s):

Type 2 Diabetes ◽

Thyroid Cancer ◽

Thyroid Disease ◽

Observational Studies ◽

Mendelian Randomization ◽

European Ancestry ◽

Uk Biobank ◽

Reverse Causality ◽

The Uk

Abstract Background The incidence of thyroid cancer is rising, and relatively little is known about modifiable risk factors for the condition. Observational studies have suggested a link between adiposity and thyroid cancer; however, these are subject to confounding and reverse causality. Here, we used data from the UK Biobank and Mendelian randomization approaches to investigate whether adiposity causes benign nodular thyroid disease and differentiated thyroid cancer. Methods We analyzed data from 379 708 unrelated participants of European ancestry in the UK Biobank and identified 1812 participants with benign nodular thyroid disease and 425 with differentiated thyroid carcinoma. We tested observational associations with measures of adiposity and type 2 diabetes mellitus. One and 2-sample Mendelian randomization approaches were used to investigate causal relationships. Results Observationally, there were positive associations between higher body mass index (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.08-1.22), higher waist-hip ratio (OR, 1.16; 95% CI, 1.09-1.23), and benign nodular thyroid disease, but not thyroid cancer. Mendelian randomization did not support a causal link for obesity with benign nodular thyroid disease or thyroid cancer, although it did provide some evidence that individuals in the highest quartile for genetic liability of type 2 diabetes had higher odds of thyroid cancer than those in the lowest quartile (OR, 1.45; CI, 1.11-1.90). Conclusions Contrary to the findings of observational studies, our results do not confirm a causal role for obesity in benign nodular thyroid disease or thyroid cancer. They do, however, suggest a link between type 2 diabetes and thyroid cancer.

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Low-density lipoprotein cholesterol and atrial fibrillation; A Mendelian randomization study using UK-Biobank data

International Journal for Population Data Science ◽

10.23889/ijpds.v1i1.322 ◽

2017 ◽

Vol 1 (1) ◽

Author(s):

Michail Katsoulis ◽

Spiros Denaxas ◽

Riyaz Patel ◽

Harry Hemingway

Keyword(s):

Atrial Fibrillation ◽

Mendelian Randomization ◽

Causal Effect ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Hospital Episode Statistics ◽

Uk Biobank ◽

Low Density Lipoprotein Cholesterol ◽

Hospital Episode ◽

The Uk

ABSTRACTObjectivesWe used data from UK-Biobank that were linked with Hospital Episode Statistics and Office for National Statistics to assess the relationship between low-density lipoprotein cholesterol (LDL-C) and atrial fibrillation (AF). In this study, we applied Mendelian randomization in order to find out whether there is a causal effect of LDL-C to AF. ApproachWe used data from the UK Biobank (~500,000 subjects) which is linked with electronic health records. At baseline (2006-2010), participants from across the UK took part in this project. They have undergone measures, provided blood, urine and saliva samples for future analysis, detailed information about themselves and agreed to have their health followed. Information in relation to the development of atrial fibrillation was derived from a) the enrollment of the participants (self-reported events), b) their hospitalization before and after their recruitment to UK-Biobank (confirmed events from Hospital Episode Statistics) and c) the death certificates [confirmed events from Office for National Statistics]. We also used genetic data from the analyses of the participants’ blood sample that have been stored. We used Mendelian randomization to capture the effect of LDL-C to AF. As instruments, we used a genetic predisposition risk score (GPRs) for LDL-C, which was created as a weighted sum of the 18 most significant SNPs related to LDL-C, as there were documented in Global Lipid Consortium, in 18 out of 22 chromosomes. We ran a logistic regression model, using AF as outcome and GPRs as exposure. ResultsOur final sample consisted of 144,092 individuals, for which we have valid information for their genetic data. The AF cases in this sample were 3207, most of which were identified from Hospital Episode Statistics (hospitalization of the participants). From the Mendelian randomization study, from our preliminary results, we found a weak positive relationship between GPRs and AF, when we did not adjust for any covariate [OR per one unit increase of GPRs=1.08, 95% CI= (0.95-1.22)] and results remained practically the same when we adjusted for age and sex [OR=1.09, 95% CI= (0.96-1.24 )]. ConclusionWe observed a weak positive association between LDL-C and AF in this study. This is the first Mendelian randomization approach that focuses on this relationship. More Mendelian randomization studies should be performed in order to identify the causal effect of LDL-C to AF. The use of electronic health records will facilitate the conduction of similar studies.

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Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

PLoS Medicine ◽

10.1371/journal.pmed.1003553 ◽

2021 ◽

Vol 18 (3) ◽

pp. e1003553

Author(s):

Aaron Leong ◽

Joanne B. Cole ◽

Laura N. Brenner ◽

James B. Meigs ◽

Jose C. Florez ◽

...

Keyword(s):

Odds Ratio ◽

Mendelian Randomization ◽

Association Studies ◽

Statistical Significance ◽

Epidemiological Studies ◽

Population Based ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

The Uk

Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

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Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study

10.1101/2021.11.19.21266578 ◽

2021 ◽

Author(s):

Min Seo Kim ◽

Minku Song ◽

Soyeon Kim ◽

Beomsu Kim ◽

Wonseok Kang ◽

...

Keyword(s):

Gastric Cancer ◽

Liver Disease ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Uk Biobank ◽

Alcoholic Fatty Liver ◽

Increased Risk

Objectives: We applied Mendelian randomization (MR) to investigate the causal associations of body mass index (BMI) and waist circumference (WC) with 19 gastrointestinal (GI) disorders. Design: MR study. Setting: The UK Biobank, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, FinnGen consortium, and genome-wide association studies. Participants: Overall, >400,000 UK Biobank participants, >170,000 participants of Finnish descent, and numerous consortia participants with predominantly European ancestry. Interventions: Single-nucleotide polymorphisms associated with BMI and WC were used as instrumental variables to estimate the causal associations with the GI conditions. Main outcome measures: Risk of developing 19 GI diseases Results: After correction for multiple testing (Bonferroni-corrected threshold of P<0.05/19) and testing for consistencies using several MR methods with varying assumptions (inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO), genetically predicted BMI was associated with increased risks of non-alcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. The odds ratio (OR) per one standard deviation (SD) increased in genetically predicted BMI (4.77 kg/m2) from 1.22 (95% confidence interval [CI] 1.12 to 1.34; P<0.0001) for NAFLD to 1.65 (95% CI 1.31 to 2.06; P<0.0001) for cholecystitis. Genetically predicted WC was associated with increased risks of NAFLD, alcoholic liver disease (ALD), cholecystitis, cholelithiasis, colon cancer, and gastric cancer. ALD was associated with WC even after adjustment for alcohol consumption in multivariable MR analysis. The OR per 1 SD increased in genetically predicted WC (12.52 cm) from 1.41 (95% CI 1.17 to 1.70; P=0.0015) for gastric cancer to 1.74 (95% CI 1.21 to 1.78; P<0.0001) for cholelithiasis. Conclusions: Higher BMI and WC are causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism. Abdominal obesity measured by WC might be more influential and relevant with a diverse span of GI diseases than BMI, highlighting a possible pathophysiological role of visceral abdominal fats in the development of GI disorders and cancers.

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Impact of Genetically Predicted Red Blood Cell Traits on Venous Thromboembolism: Multivariable Mendelian Randomization Study Using UK Biobank

Journal of the American Heart Association ◽

10.1161/jaha.120.016771 ◽

2020 ◽

Vol 9 (14) ◽

Author(s):

Shan Luo ◽

Shiu Lun Au Yeung ◽

Verena Zuber ◽

Stephen Burgess ◽

Catherine Mary Schooling

Keyword(s):

Venous Thromboembolism ◽

General Population ◽

Blood Cell ◽

Red Blood Cell ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

European Ancestry ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

Background Red blood cell (RBC) transfusion and erythropoiesis‐stimulating agent administration are cornerstones of clinical practice, yet concerns exist as to potential increased risk of thrombotic events. This study aims to identify RBC traits most relevant to venous thromboembolism (VTE) and assess their genetically predicted effects on VTE in the general population. Methods and Results We used multivariable mendelian randomization with bayesian model averaging for exposure selection. We obtained genetic variants predicting any of 12 RBC traits from the largest genome‐wide association study of hematological traits (173 480 participants of European ancestry) and applied them to the UK Biobank (265 424 white British participants). We used univariable mendelian randomization methods as sensitivity analyses for validation. Among 265 424 unrelated participants in the UK Biobank, there were 9752 cases of VTE (4490 men and 5262 women). Hemoglobin was selected as the plausible important RBC trait for VTE (marginal inclusion probability=0.91). The best‐fitting model across all RBC traits contained hemoglobin only (posterior probability=0.46). Using the inverse variance–weighted method, genetically predicted hemoglobin was positively associated (odds ratio, 1.21 per g/dL unit of hemoglobin; 95% CI, 1.05–1.41) with VTE. Sensitivity analyses (mendelian randomization–Egger, weighted median, and mendelian randomization pleiotropy residual sum and outlier test) gave consistent estimates. Conclusions Endogenous hemoglobin is the key RBC trait causing VTE, with a detrimental effect in the general population on VTE. Given men have higher hemoglobin than women, this finding may help explain the sexual disparity in VTE rates. The benefits of therapies and other factors that raise hemoglobin need to be weighed against their risks.

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Relationship between Serum 25(OH)D and Depression: Causal Evidence from a Bi-Directional Mendelian Randomization Study

Nutrients ◽

10.3390/nu13010109 ◽

2020 ◽

Vol 13 (1) ◽

pp. 109

Author(s):

Anwar Mulugeta ◽

Amanda Lumsden ◽

Elina Hyppönen

Keyword(s):

Vitamin D ◽

Mendelian Randomization ◽

Causal Effect ◽

Uk Biobank ◽

Reverse Causality ◽

Hydroxyvitamin D ◽

Inverse Variance ◽

The Uk ◽

Genetically Determined ◽

The Relationship

The relationship between depression and vitamin D deficiency is complex, with evidence mostly from studies affected by confounding and reverse causality. We examined the causality and direction of the relationship between 25-hydroxyvitamin D (25(OH)D) and depression in bi-directional Mendelian randomization (MR) analyses using information from up to 307,618 white British participants from the UK Biobank and summary results from the SUNLIGHT (n = 79,366) and Psychiatric Genomics consortia (PGC 113,154 cases and 218,523 controls). In observational analysis, the odds of depression decreased with higher 25(OH)D concentrations (adjusted odds ratio (OR) per 50% increase 0.95, 95%CI 0.94–0.96). In MR inverse variance weighted (IVW) using the UK Biobank, there was no association between genetically determined serum 25(OH)D and depression (OR per 50% higher 0.97, 95%CI 0.90–1.05) with consistent null association across all MR approaches and in data from PGC consortium. In contrast, genetic liability to depression was associated with lower 25(OH)D concentrations (MR IVW −3.26%, −4.94%–−1.55%), with the estimates remaining generally consistent after meta-analysing with the consortia. In conclusion, we found genetic evidence for a causal effect of depression on lower 25(OH)D concentrations, however we could not confirm a beneficial effect of nutritional vitamin D status on depression risk.

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Causality of Abdominal Obesity on Cognition: a Trans-ethnic Mendelian Randomization study

10.1101/2021.10.13.21264895 ◽

2021 ◽

Author(s):

Shi-Heng Wang ◽

Mei-Hsin Su ◽

Chia-Yen Chen ◽

Yen-Feng Lin ◽

Yen-Chen Anne Feng ◽

...

Keyword(s):

Cognitive Aging ◽

Observational Studies ◽

Mendelian Randomization ◽

Causal Effect ◽

European Ancestry ◽

P Value ◽

Abdominal Adiposity ◽

Uk Biobank ◽

Reverse Causality ◽

Summary Data

Obesity has been associated with cognition in observational studies; however, whether its effect is confounding, reverse causality, or causal remains inconclusive. Using two-sample Mendelian randomization (MR) analyses, we investigated the causality of overall obesity, measured by BMI, and abdominal adiposity, measured by waist-hip ratio adjusted for BMI (WHRadjBMI), on cognition. Using summary data from the GIANT consortium, COGENT consortium, and UK Biobank of European ancestry, there was no causal effect of BMI on cognition performance (beta[95% CI]=-0.04[-0.12,0.04], p-value=0.35); however, a 1-SD increase in WHRadjBMI was associated with 0.07 standardized decrease in cognition performance (beta[95% CI]=-0.07[-0.12,-0.02], p=0.006). Using raw data from the Taiwan Biobank of Asian ancestry, there was no causal effect of BMI on cognitive aging (beta[95% CI]=0.00[-0.09,0.09], p-value=0.95); however, a 1-SD increase in WHRadjBMI was associated with a 0.17 standardized decrease in cognitive aging (beta[95% CI]=-0.17[-0.30,-0.03], p=0.02). This trans-ethnic MR study reveals that abdominal adiposity impairs cognition.

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Genetically-Determined Serum Calcium Levels and Markers of Ventricular Repolarisation: A Mendelian Randomization Study in the UK Biobank

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.003231 ◽

2021 ◽

Author(s):

William J. Young ◽

Helen R. Warren ◽

Dennis O. Mook-Kanamori ◽

Julia Ramírez ◽

Stefan van Duijvenboden ◽

...

Keyword(s):

Serum Calcium ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Disease Risk ◽

Causal Effect ◽

Sensitivity Analyses ◽

European Ancestry ◽

Uk Biobank ◽

Ventricular Repolarisation ◽

Increased Risk

Background - Electrocardiographic (ECG) markers of ventricular depolarisation and repolarisation are associated with an increased risk of arrhythmia and sudden cardiac death. Our prior work indicated lower serum calcium concentrations are associated with longer QT and JT intervals in the general population. Here, we investigate whether serum calcium is a causal risk factor for changes in ECG measures using Mendelian Randomization (MR). Methods - Independent lead variants from a newly performed genome-wide association study (GWAS) for serum calcium in >300,000 European-ancestry participants from UK-Biobank were used as instrumental variables. Two-sample MR analyses were performed to approximate the causal effect of serum calcium on QT, JT and QRS intervals using an inverse-weighted method in 76,226 participants not contributing to the serum calcium GWAS. Sensitivity analyses including MR-Egger, weighted-median estimator, and MR-PRESSO were performed to test for the presence of horizontal pleiotropy. Results - 205 independent lead calcium-associated variants were used as instrumental variables for MR. A decrease of 0.1 mmol/L serum calcium was associated with longer QT (3.01ms (95% CI 3.99, -2.03) and JT (2.89ms (-3.87, - 1.91) intervals. A weak association was observed for QRS duration (secondary analyses only). Results were concordant in all sensitivity analyses. Conclusions - These analyses support a causal effect of serum calcium levels on ventricular repolarisation, in a middle-aged population of European-ancestry where serum calcium concentrations are likely stable and chronic. Modulation of calcium concentration may therefore directly influence cardiovascular disease risk.

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Clustered Mendelian Randomization analyses identifies distinct and opposing pathways in the causal association between insulin-like growth factor-1 and type 2 diabetes mellitus

10.1101/2021.05.12.21257093 ◽

2021 ◽

Author(s):

Wenyi Wang ◽

Ephrem Baraki Tesfay ◽

Ko Willems van Dijk ◽

Andrzej Bartke ◽

Diana van Heemst ◽

...

Keyword(s):

Type 2 Diabetes ◽

Growth Factor ◽

Mendelian Randomization ◽

Causal Effect ◽

Proportional Hazard ◽

Uk Biobank ◽

Heterogeneous Distribution ◽

Cox Proportional Hazard ◽

The Uk

Aims/hypothesis: There is inconsistent evidence for the causal role of serum insulin-like growth factor-1 (IGF-1) concentration in the pathogenesis of type 2 diabetes. Here, we investigated the association between IGF-1 and type 2 diabetes using a combination of multivariable-adjusted and (clustered) Mendelian Randomization (MR) analyses in the UK Biobank. Methods: We conducted Cox proportional hazard analyses in 451,232 European-ancestry individuals of the UK Biobank (55.3% women, mean age at recruitment 56.6 years), among which 13,247 individuals developed type 2 diabetes during up to 12 years of follow-up. In addition, we conducted two-sample MR analyses based on independent SNPs associated with IGF-1. Given the heterogeneity between the causal estimates of individual instruments (P-value for Q statistic=4.03e-145), we also conducted clustered MR analyses. Biological pathway analyses of the identified clusters were performed by overrepresentation analyses. Results: In the Cox proportional hazard models, with IGF-1 concentrations stratified in quintiles, we observed that participants in the lowest quintile had the highest relative risk of type 2 diabetes (HR: 1.31; CI: 1.23-1.39). In contrast, in the two-sample MR analyses, higher genetically-influenced IGF-1 was associated with a higher risk of type 2 diabetes. Based on the heterogeneous distribution of causal effect estimates, six clusters associated either with a lower or a higher risk of type 2 diabetes were identified. The main clusters in which a higher IGF-1 was associated with a lower risk of type 2 diabetes consisted of instruments mapping to genes in the growth-hormone signaling pathway, whereas the main clusters in which a higher IGF-1 was associated with a higher risk of type 2 diabetes consisted of instruments mapping to genes in pathways related to amino acid metabolism and genomic integrity. Conclusion: The IGF-1 associated SNPs used as genetic instruments in MR analyses showed a heterogeneous distribution of causal effect estimates on the risk of type 2 diabetes. This was likely explained by differences in the underlying molecular pathways that increase IGF-1 concentration and differentially mediate the effects of IGF-1 on type 2 diabetes.

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