Publications
282 results found
Ciofani JL, Han D, Allahwala UK, et al., 2023, Lipids, Blood Pressure, and Diabetes Mellitus on Risk of Cardiovascular Diseases in East Asians: A Mendelian Randomization Study., Am J Cardiol, Vol: 205, Pages: 329-337
Elevated blood pressure, dyslipidemia, and impaired glycemic control are well-established cardiovascular risk factors in Europeans, but there are comparatively few studies focused on East Asian populations. This study evaluated the potential causal relations between traditional cardiovascular risk factors and disease risk in East Asians through a 2-sample Mendelian randomization approach. We collected summary statistics for blood pressure parameters, lipid subsets, and type 2 diabetes mellitus liability from large genome-wide association study meta-analyses conducted in East Asians and Europeans. These were paired with summary statistics for ischemic heart disease (IHD), ischemic stroke (IS), peripheral vascular disease, heart failure (HF) and atrial fibrillation (AF). We performed univariable Mendelian randomization analyses for each exposure-outcome pair, followed by multivariable analyses for the available lipid subsets. The genetically predicted risk factors associated with IHD and AF were similar between East Asians and Europeans. However, in East Asians only genetically predicted elevated blood pressure was significantly associated with IS (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001) and HF (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001), whereas nearly all genetically predicted risk factors were significantly associated with IS and HF in Europeans. In conclusion, this study provides supportive evidence for similar causal relations between traditional cardiovascular risk factors and IHD and AF in both East Asian and European ancestry populations. However, the identified risk factors for IS and HF differed between East Asians and Europeans, potentially highlighting distinct disease etiologies between these populations.
Gill D, Woolf B, Zagkos L, et al., 2023, The cardiovascular efficacy of lipid-lowering drug targets is not entirely explained by apolipoprotein B reduction: Mendelian randomization evidence, Circulation: Genomic and Precision Medicine, ISSN: 2574-8300
Woolf B, Cronjé HT, Zagkos L, et al., 2023, Appraising the causal relationship between plasma caffeine levels and neuropsychiatric disorders through Mendelian randomization., BMC Med, Vol: 21
BACKGROUND: Caffeine exposure modifies the turnover of monoamine neurotransmitters, which play a role in several neuropsychiatric disorders. We conducted a Mendelian randomization study to investigate whether higher plasma caffeine levels are causally associated with the risk of anorexia nervosa, bipolar disorder, major depressive disorder (MDD), and schizophrenia. METHODS: Summary-level data on the neuropsychiatric disorders were obtained from large-scale genome-wide association studies (GWASs) of European ancestry participants (n = 72,517 to 807,553) and meta-analyzed with the corresponding data from the FinnGen study (n = 356,077). Summary-level data on plasma caffeine were extracted from a GWAS meta-analysis of 9876 European ancestry individuals. The Mendelian randomization analyses estimated the Wald ratio for each genetic variant and meta-analyzed the variant-specific estimates using multiplicative random effects meta-analysis. RESULTS: After correcting for multiple testing, genetically predicted higher plasma caffeine levels were associated with higher odds of anorexia nervosa (odds ratio [OR] = 1.124; 95% confidence interval [CI] = 1.024-1.238, pFDR = 0.039) and a lower odds of bipolar disorder (OR = 0.905, 95% CI = 0.827-0.929, pFDR = 0.041) and MDD (OR = 0.965, 95% CI = 0.937-0.995, pFDR = 0.039). Instrumented plasma caffeine levels were not associated with schizophrenia (OR = 0.986, 95% CI = 0.929-1.047, pFDR = 0.646). CONCLUSIONS: These Mendelian randomization findings indicate that long-term higher plasma caffeine levels may lower the risk of bipolar disorder and MDD but increase the risk of anorexia nervosa. These results warrant further research to explore whether caffeine consumption, supplementation, or abstinence could render clinically relevant therapeuti
Burgess S, Davey Smith G, Davies NM, et al., 2023, Guidelines for performing Mendelian randomization investigations: update for summer 2023, Wellcome Open Research, Vol: 4, Pages: 186-186
<ns3:p>This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into ten sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), extensions and additional analyses, data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 24 months.</ns3:p>
Kraaijenhof JM, Opstal TSJ, Cornel JH, et al., 2023, Effect of PCSK9 Inhibition on the Plasma Proteome: A SPIRE SubStudy., Arterioscler Thromb Vasc Biol, Vol: 43, Pages: 1595-1597
Yarmolinsky J, Bouras E, Constantinescu A, et al., 2023, Genetically proxied glucose-lowering drug target perturbation and risk of cancer: a Mendelian randomisation analysis., Diabetologia, Vol: 66, Pages: 1481-1500
AIMS/HYPOTHESIS: Epidemiological studies have generated conflicting findings on the relationship between glucose-lowering medication use and cancer risk. Naturally occurring variation in genes encoding glucose-lowering drug targets can be used to investigate the effect of their pharmacological perturbation on cancer risk. METHODS: We developed genetic instruments for three glucose-lowering drug targets (peroxisome proliferator activated receptor γ [PPARG]; sulfonylurea receptor 1 [ATP binding cassette subfamily C member 8 (ABCC8)]; glucagon-like peptide 1 receptor [GLP1R]) using summary genetic association data from a genome-wide association study of type 2 diabetes in 148,726 cases and 965,732 controls in the Million Veteran Program. Genetic instruments were constructed using cis-acting genome-wide significant (p<5×10-8) SNPs permitted to be in weak linkage disequilibrium (r2<0.20). Summary genetic association estimates for these SNPs were obtained from genome-wide association study (GWAS) consortia for the following cancers: breast (122,977 cases, 105,974 controls); colorectal (58,221 cases, 67,694 controls); prostate (79,148 cases, 61,106 controls); and overall (i.e. site-combined) cancer (27,483 cases, 372,016 controls). Inverse-variance weighted random-effects models adjusting for linkage disequilibrium were employed to estimate causal associations between genetically proxied drug target perturbation and cancer risk. Co-localisation analysis was employed to examine robustness of findings to violations of Mendelian randomisation (MR) assumptions. A Bonferroni correction was employed as a heuristic to define associations from MR analyses as 'strong' and 'weak' evidence. RESULTS: In MR analysis, genetically proxied PPARG perturbation was weakly associated with higher risk of prostate cancer (for PPARG perturbation equivalent to a 1 unit decrease in inverse rank normal transformed HbA1c: OR 1.75 [95% CI 1.07, 2.85], p=0.02). In histological subtyp
Giontella A, Zagkos L, Geybels M, et al., 2023, Renoprotective effects of genetically proxied fibroblast growth factor 21: Mendelian randomization, proteome-wide and metabolome-wide association study., Metabolism, Vol: 145
BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). METHODS: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). RESULTS: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10-4), higher urinary sodium excretion (p = 5.1 × 10-11), and lower urine albumin-creatinine ratio (p = 3.6 × 10-5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10-4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10-07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10-24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. CONCLUSION: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re
Woolf B, Sallis HM, Munafò MR, et al., 2023, Deriving GWAS summary estimates for paternal smoking in UK biobank: a GWAS by subtraction., BMC Res Notes, Vol: 16
OBJECTIVE: To use genome-wide association study (GWAS) by subtraction, a method for deriving novel GWASs from existing summary statistics, to derive genome-wide summary statistics for paternal smoking. RESULT: A GWAS by subtraction was implemented using a weighted linear model that defined the child-genotype paternal-phenotype association as the child-genotype child-phenotype association minus the child-genotype maternal-phenotype association. We first use the laws of inherence to derive the weighted linear model. We then implemented the linear model to create a GWAS of paternal smoking by subtracting the summary statistics from a GWAS of maternal smoking from the summary statistics of a GWAS of the index individual's smoking. We used a Monte-Carlo simulation to validate the model and showed that this approach performed similarly in terms of bias to performing a traditional GWAS of paternal smoking. Finally, we validated the summary statistics in a Mendelian randomisation analysis by demonstrating an association of genetically predicted paternal smoking with paternal lung cancer and emphysema.
Woolf B, Gill D, Sallis H, et al., 2023, The UK BiLEVE and Mendelian randomisation: using multivariable instrumental variables to address "damned if you, damned if you don't" adjustment problems., BMC Res Notes, Vol: 16
OBJECTIVE: To explore the use of multivariable instrumental variables to resolve the "damned if you do, damned if you don't" adjustment problem created for Mendelian randomisation (MR) analysis using the smoking or lung function related phenotypes in the UK Biobank (UKB). RESULT: "damned if you do, damned if you don't" adjustment problems occur when both adjusting and not-adjusting for a variable will induce bias in an analysis. One instance of this occurs because the genotyping chip of UKB participants differed based on lung function/smoking status. In simulations, we show that multivariable instrumental variables analyses can attenuate potential collider bias introduced by adjusting for a proposed covariate, such as the UKB genotyping chip. We then explore the effect of adjusting for genotyping chip in a multivariable MR model exploring the effect of smoking on seven medical outcomes (lung cancer, emphysema, hypertension, stroke, heart diseases, depression, and disabilities). We additionally compare our results to a traditional univariate MR analysis using genome-wide analyses summary statistics which had and had not adjusted for genotyping chip. This analysis implies that the difference in genotyping chip has introduced only a small amount of bias.
Yuan S, Li Y, Wang L, et al., 2023, Deciphering the genetic architecture of atrial fibrillation offers insights into disease prediction, pathophysiology and downstream sequelae., medRxiv
AIMS: The study aimed to discover novel genetic loci for atrial fibrillation (AF), explore the shared genetic etiologies between AF and other cardiovascular and cardiometabolic traits, and uncover AF pathogenesis using Mendelian randomization analysis. METHODS AND RESULTS: We conducted a genome-wide association study meta-analysis including 109,787 AF cases and 1,165,920 controls of European ancestry and identified 215 loci, among which 91 were novel. We performed Genomic Structural Equation Modeling analysis between AF and four cardiovascular comorbidities (coronary artery disease, ischemic stroke, heart failure, and vneous thromboembolism) and found 189 loci shared across these diseases as well as a universal genetic locus shared by atherosclerotic outcomes (i.e., rs1537373 near CDKN2B ). Three genetic loci (rs10740129 near JMJD1C , rs2370982 near NRXN3 , and rs9931494 near FTO ) were associated with AF and cardiometabolic traits. A polygenic risk score derived from this genome-wide meta-analysis was associated with AF risk (odds ratio 2.36, 95% confidence interval 2.31-2.41 per standard deviation increase) in the UK biobank. This score, combined with age, sex, and basic clinical features, predicted AF risk (AUC 0.784, 95% CI 0.781-0.787) in Europeans. Phenome-wide association analysis of the polygenic risk score identified many AF-related comorbidities of the circulatory, endocrine, and respiratory systems. Phenome-wide and multi-omic Mendelian randomization analyses identified associations of blood lipids and pressure, diabetes, insomnia, obesity, short sleep, and smoking, 27 blood proteins, one gut microbe ( genus.Catenibacterium ), and 11 blood metabolites with risk to AF. CONCLUSIONS: This genome-wide association study and trans-omic Mendelian randomization analysis provides insights into disease risk prediction, pathophysiology and downstream sequelae.
Corpas M, Siddiqui MK, Soremekun O, et al., 2023, Addressing Ancestry and Sex Bias in Pharmacogenomics., Annu Rev Pharmacol Toxicol
The association of an individual's genetic makeup with their response to drugs is referred to as pharmacogenomics. By understanding the relationship between genetic variants and drug efficacy or toxicity, we are able to optimize pharmacological therapy according to an individual's genotype. Pharmacogenomics research has historically suffered from bias and underrepresentation of people from certain ancestry groups and of the female sex. These biases can arise from factors such as drugs and indications studied, selection of study participants, and methods used to collect and analyze data. To examine the representation of biogeographical populations in pharmacogenomic data sets, we describe individuals involved in gene-drug response studies from PharmGKB, a leading repository of drug-gene annotations, and showcase CYP2D6, a gene that metabolizes approximately 25% of all prescribed drugs. We also show how the historical underrepresentation of females in clinical trials has led to significantly more adverse drug reactions in females than in males. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Zuber V, Lewin A, Levin MG, et al., 2023, Multi-response Mendelian randomization: Identification of shared and distinct exposures for multimorbidity and multiple related disease outcomes, American Journal of Human Genetics, Vol: 110, Pages: 1177-1199, ISSN: 0002-9297
The existing framework of Mendelian randomization (MR) infers the causal effect of one or multiple exposures on one single outcome. It is not designed to jointly model multiple outcomes, as would be necessary to detect causes of more than one outcome and would be relevant to model multimorbidity or other related disease outcomes. Here, we introduce multi-response Mendelian randomization (MR2), an MR method specifically designed for multiple outcomes to identify exposures that cause more than one outcome or, conversely, exposures that exert their effect on distinct responses. MR2 uses a sparse Bayesian Gaussian copula regression framework to detect causal effects while estimating the residual correlation between summary-level outcomes, i.e., the correlation that cannot be explained by the exposures, and vice versa. We show both theoretically and in a comprehensive simulation study how unmeasured shared pleiotropy induces residual correlation between outcomes irrespective of sample overlap. We also reveal how non-genetic factors that affect more than one outcome contribute to their correlation. We demonstrate that by accounting for residual correlation, MR2 has higher power to detect shared exposures causing more than one outcome. It also provides more accurate causal effect estimates than existing methods that ignore the dependence between related responses. Finally, we illustrate how MR2 detects shared and distinct causal exposures for five cardiovascular diseases in two applications considering cardiometabolic and lipidomic exposures and uncovers residual correlation between summary-level outcomes reflecting known relationships between cardiovascular diseases.
Soremekun O, Musanabaganwa C, Uwineza A, et al., 2023, A Mendelian randomization study of genetic liability to post-traumatic stress disorder and risk of ischemic stroke., Transl Psychiatry, Vol: 13
Observational studies have shown an association between post-traumatic stress disorder (PTSD) and ischemic stroke (IS) but given the susceptibility to confounding it is unclear if these associations represent causal effects. Mendelian randomization (MR) facilitates causal inference that is robust to the influence of confounding. Using two sample MR, we investigated the causal effect of genetic liability to PTSD on IS risk. Ancestry-specific genetic instruments of PTSD and four quantitative sub-phenotypes of PTSD, including hyperarousal, avoidance, re-experiencing, and total symptom severity score (PCL-Total) were obtained from the Million Veteran Programme (MVP) using a threshold P value (P) of <5 × 10-7, clumping distance of 1000 kilobase (Mb) and r2 < 0.01. Genetic association estimates for IS were obtained from the MEGASTROKE consortium (Ncases = 34,217, Ncontrols = 406,111) for European ancestry individuals and from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) (Ncases = 3734, Ncontrols = 18,317) for African ancestry individuals. We used the inverse-variance weighted (IVW) approach as the main analysis and performed MR-Egger and the weighted median methods as pleiotropy-robust sensitivity analyses. In European ancestry individuals, we found evidence of an association between genetic liability to PTSD avoidance, and PCL-Total and increased IS risk (odds ratio (OR)1.04, 95% Confidence Interval (CI) 1.007-1.077, P = 0.017 for avoidance and (OR 1.02, 95% CI 1.010-1.040, P = 7.6 × 10-4 for PCL total). In African ancestry individuals, we found evidence of an association between genetically liability to PCL-Total and reduced IS risk (OR 0.95 (95% CI 0.923-0.991, P = 0.01) and hyperarousal (OR 0.83 (95% CI 0.691-0.991, P = 0.039) but no association was obser
Daghlas I, Gill D, 2023, Leveraging genetic predictors of factor XI levels to anticipate results from clinical trials, European Journal of Neurology, Vol: 30, Pages: 2112-2116, ISSN: 1351-5101
BACKGROUND: Factor XI (FXI) is a promising therapeutic target for the prevention of thrombotic disease without increasing bleeding risk. METHODS: We performed Mendelian randomization (MR) analyses to investigate the association of genetically predicted reductions in FXI levels with risk of venous thromboembolism, ischemic stroke, bleeding outcomes, and lifespan. RESULTS: Genetically predicted reductions in FXI levels were associated with lower risk of ischemic stroke (odds ratio per 1 standard deviation (SD) lower serum FXI 0.90, 95% confidence interval 0.87-0.93, p = 1.59 × 10-11 ), and venous thromboembolism (0.54, 0.49-0.59, p = 2.13 × 10-39 ) but did not associate with increased bleeding risk (p > 0.16). Genetically predicted reductions in serum FXI levels associated with longer lifespan (0.37 years per 1 SD lower serum FXI, 0.13-0.61, p = 0.003). CONCLUSIONS: These genetic data support FXI as a potentially efficacious and safe therapeutic target and anticipate positive results from ongoing phase 3 clinical trials.
Daghlas I, Nassan M, Gill D, 2023, Genetically proxied lean mass and risk of Alzheimer’s disease: a Mendelian randomization study, BMJ Medicine, Vol: 2, Pages: 1-9, ISSN: 2754-0413
Objectives – To examine whether genetically proxied lean mass is associated with risk of Alzheimer’s disease.Design – Two-sample Mendelian randomization (MR) study.Setting – The UK Biobank study and genome-wide association study meta-analyses of Alzheimer’s disease (AD) and intelligence.Participants – Summary-level genetic data from 1) 450,243 UK Biobank participants with impedance measures of lean mass and fat mass, 2) an independent sample of 21,982 cases of AD and 41,944 controls without Alzheimer’s disease, 3) a replication sample of 7,329 cases of AD and 252,879 controls, and 4) 269,867 individuals partaking in a genome-wide association study of intelligence.Exposure – Genetic variants proxying variation in lean mass.Main outcome measures – Clinically diagnosed Alzheimer’s disease.Results - A one-standard deviation increase in genetically proxied appendicular lean mass (ALM) was associated with a 12% reduced risk of Alzheimer’s disease (odds ratio 0.88, 95% confidence interval 0.82-0.95, P=5x10-4). This finding was replicated in an independent AD cohort (0.89, 0.81-0.99, P=0.03) and was consistent in sensitivity analyses more robust to the inclusion of pleiotropic variants. Adjusting for potential mediation through genetically proxied intelligence did not attenuate the effect of ALM on AD. Higher genetically proxied ALM was also associated with increased intelligence (standard deviation increase in intelligence per standard deviation increase in ALM 0.09, 95% confidence interval 0.06-0.11, P=2.09x10-4), and adjusting for potential mediation through genetically liability to AD did not attenuate this association. We found similar results for the outcomes of AD and intelligence when using the exposures of genetically proxied trunk lean mass and whole-body lean mass respectively, adjusted for genetically proxied fat mass.Conclusions – These findings support that lean mass as a possible modifiab
Rogers M, Gill D, Ahlqvist E, et al., 2023, Genetically proxied impaired GIPR signaling and risk of 6 cancers., iScience, Vol: 26
Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
Wang M, Zhang Z, Liu D, et al., 2023, Soluble adhesion molecules and functional outcome after ischemic stroke: A Mendelian randomization study., J Stroke Cerebrovasc Dis, Vol: 32
OBJECTIVES: We employed Mendelian randomization to determine whether genetically predicted circulating levels of endothelial-derived adhesion molecules (soluble intercellular adhesion molecule-1 [sICAM-1]), soluble vascular-leukocyte adhesion molecule-1 [sVCAM-1], and soluble-endothelial-leukocyte adhesion molecule [sE-selectin]) were associated with functional outcome after ischemic stroke. METHODS: Independent genetic variants robustly associated with soluble adhesion molecules, located at or close to the coding gene (cis), were used as genetic instruments. The functional outcome was evaluated using the 3-month modified Rankin Scale (mRS) score after ischemic stroke. A poor functional outcome was defined as mRS ≥ 3 at 3 months. We extracted summary data for functional outcome after ischemic stroke from the Genetics of Ischaemic Stroke Functional Outcome network (n = 6,021). RESULTS: Genetically elevated sICAM-1 (OR 1.28, 95% CI 1.05-1.56) and sE-selectin (OR 2.69, 95% CI 1.23-5.86) levels were related with poor post-stroke outcome. However, we found no evidence that genetically elevated sVCAM-1 were associated with post-stroke outcome (OR 1.36, 95% CI 0.39-4.66). CONCLUSIONS: We found that genetically elevated higher sICAM-1 and sE-selectin levels are associated with poor post-stroke outcome. Further studies are warranted to evaluate the potential of ICAM-1 and E-selectin to be drug targets for post-stroke recovery.
Cronjé HT, Gill D, 2023, Role of Clonal Hematopoiesis of Indeterminant Potential-Related Germline TET2 Variation in Inflammation and Cardiovascular Disease Risk: A Mendelian Randomization Study., Arterioscler Thromb Vasc Biol, Vol: 43, Pages: e227-e229
Karageorgiou V, Gill D, Bowden J, et al., 2023, Sparse dimensionality reduction approaches in Mendelian randomization with highly correlated exposures., eLife, Vol: 12, Pages: 1-35, ISSN: 2050-084X
Multivariable Mendelian randomization (MVMR) is an instrumental variable technique that generalizes the MR framework for multiple exposures. Framed as a linear regression problem, it is subject to the pitfall of multi-collinearity. The bias and efficiency of MVMR estimates thus depends heavily on the correlation of exposures. Dimensionality reduction techniques such as principal component analysis (PCA) provide transformations of all the included variables that are effectively uncorrelated. We propose the use of sparse PCA (sPCA) algorithms that create principal components of subsets of the exposures with the aim of providing more interpretable and reliable MR estimates. The approach consists of three steps. We first apply a sparse dimension reduction method and transform the variant-exposure summary statistics to principal components. We then choose a subset of the principal components based on data-driven cutoffs, and estimate their strength as instruments with an adjusted F-statistic. Finally, we perform MR with these transformed exposures. This pipeline is demonstrated in a simulation study of highly correlated exposures and an applied example using summary data from a genome-wide association study of 97 highly correlated lipid metabolites. As a positive control, we tested the causal associations of the transformed exposures on CHD. Compared to the conventional inverse-variance weighted MVMR method and a weak-instrument robust MVMR method (MR GRAPPLE), sparse component analysis achieved a superior balance of sparsity and biologically insightful grouping of the lipid traits.
Le NN, Tran TQB, du Toit C, et al., 2023, Establishing plausibility of cardiovascular adverse effects of immunotherapies using Mendelian randomisation, Frontiers in Cardiovascular Medicine, Vol: 10, ISSN: 2297-055X
Immune checkpoint inhibitors (ICIs) and Janus kinase inhibitors (JAKis) have raised concerns over serious unexpected cardiovascular adverse events. The widespread pleiotropy in genome-wide association studies offers an opportunity to identify cardiovascular risks from in-development drugs to help inform appropriate trial design and pharmacovigilance strategies. This study uses the Mendelian randomization (MR) approach to study the causal effects of 9 cardiovascular risk factors on ischemic stroke risk both independently and by mediation, followed by an interrogation of the implicated expression quantitative trait loci (eQTLs) to determine if the enriched pathways can explain the adverse stroke events observed with ICI or JAKi treatment. Genetic predisposition to higher systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), waist-to-hip ratio (WHR), low-density lipoprotein cholesterol (LDL), triglycerides (TG), type 2 diabetes (T2DM), and smoking index were associated with higher ischemic stroke risk. The associations of genetically predicted BMI, WHR, and TG on the outcome were attenuated after adjusting for genetically predicted T2DM [BMI: 53.15% mediated, 95% CI 17.21%-89.10%; WHR: 42.92% (4.17%-81.67%); TG: 72.05% (10.63%-133.46%)]. JAKis, programmed cell death protein 1 and programmed death ligand 1 inhibitors were implicated in the pathways enriched by the genes related to the instruments for each of SBP, DBP, WHR, T2DM, and LDL. Overall, MR mediation analyses support the role of T2DM in mediating the effects of BMI, WHR, and TG on ischemic stroke risk and follow-up pathway enrichment analysis highlights the utility of this approach in the early identification of potential harm from drugs.
Au Yeung SL, Gill D, 2023, Standardizing the reporting of Mendelian randomization studies, BMC Medicine, Vol: 21, ISSN: 1741-7015
Cronjé HT, Karhunen V, Hovingh GK, et al., 2023, Genetic evidence implicating natriuretic peptide receptor-3 in cardiovascular disease risk: a Mendelian randomization study, BMC Medicine, Vol: 21, ISSN: 1741-7015
Background:C-type natriuretic peptide (CNP) is a known target for promoting growth and has been implicated as a therapeutic opportunity for the prevention and treatment of cardiovascular disease (CVD). This study aimed to explore the effect of CNP on CVD risk using the Mendelian randomization (MR) framework.MethodsInstrumental variables mimicking the effects of pharmacological intervention on CNP were identified as uncorrelated genetic variants located in the genes coding for its primary receptors, natriuretic peptide receptors-2 and 3 (NPR2 and NPR3), that associated with height. We performed MR and colocalization analyses to investigate the effects of NPR2 signalling and NPR3 function on CVD outcomes and risk factors. MR estimates were compared to those obtained when considering height variants from throughout the genome.Results:Genetically-proxied reduced NPR3 function was associated with a lower risk of CVD, with odds ratio (OR) 0.74 per standard deviation (SD) higher NPR3-predicted height, and 95% confidence interval (95% CI) 0.64–0.86. This effect was greater in magnitude than observed when considering height variants from throughout the genome. For CVD subtypes, similar MR associations for NPR3-predicted height were observed when considering the outcomes of coronary artery disease (0.75, 95% CI 0.60–0.92), stroke (0.69, 95% CI 0.50–0.95) and heart failure (0.77, 95% CI 0.58–1.02). Consideration of CVD risk factors identified systolic blood pressure (SBP) as a potential mediator of the NPR3-related CVD risk lowering. For stroke, we found that the MR estimate for NPR3 was greater in magnitude than could be explained by a genetically predicted SBP effect alone. Colocalization results largely supported the MR findings, with no evidence of results being driven by effects due to variants in linkage disequilibrium. There was no MR evidence supporting effects of NPR2 on CVD risk, although this null finding could be attributable to fewer geneti
Chen J, Yuan S, Fu T, et al., 2023, Gastrointestinal Consequences of Type 2 Diabetes Mellitus and Impaired Glycemic Homeostasis: A Mendelian Randomization Study., Diabetes Care, Vol: 46, Pages: 828-835
OBJECTIVE: We conducted a Mendelian randomization (MR) study to examine the associations of type 2 diabetes and glycemic traits with gastrointestinal diseases (GDs). RESEARCH DESIGN AND METHODS: Uncorrelated genetic variants associated with type 2 diabetes (n = 231), fasting insulin (n = 38), fasting glucose (n = 71), and hemoglobin A1c (n = 75) at the genome-wide significance were selected as instrument variables. Genetic associations with 23 common GDs were obtained from the FinnGen and UK Biobank studies and other large consortia. RESULTS: Genetic liability to type 2 diabetes was associated with the risk of 12 GDs. Per 1-unit increase in the log-transformed odds ratio (OR) of type 2 diabetes, the OR was 1.06 (95% CI, 1.03-1.09) for gastroesophageal reflux disease, 1.12 (95% CI, 1.07-1.17) for gastric ulcer, 1.11 (95% CI, 1.03-1.20) for acute gastritis, 1.07 (95% CI, 1.01-1.13) for chronic gastritis, 1.08 (95% CI, 1.03-1.12) for irritable bowel syndrome, 1.04 (95% CI, 1.01-1.07) for diverticular disease, 1.08 (95% CI, 1.02-1.14) for acute pancreatitis, 1.09 (95% CI, 1.05-1.12) for cholelithiasis, 1.09 (95% CI, 1.05-1.13) for cholelithiasis with cholecystitis, 1.29 (95% CI, 1.17-1.43) for nonalcoholic fatty liver disease, 1.12 (95% CI, 1.03-1.21) for liver cirrhosis, and 0.93 (95% CI, 0.89-0.97) for ulcerative colitis. Genetically predicted higher levels of fasting insulin and glucose were associated with six and one GDs, respectively. CONCLUSIONS: Associations were found between genetic liability to type 2 diabetes and an increased risk of a broad range of GDs, highlighting the importance of GD prevention in patients with type 2 diabetes.
Cao L, Liu D, Karhunen V, et al., 2023, Circulating macrophage colony-stimulating factor levels and stroke: A Mendelian randomization study., J Stroke Cerebrovasc Dis, Vol: 32
OBJECTIVES: Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor, has been shown to be associated with risk of ischemic stroke in conventional epidemiological study. We performed a Mendelian randomization analysis to evaluate the effects of genetically predicted circulating CSF1 levels on stroke and carotid intima-media thickness (cIMT). METHODS: Genetic variants robustly associated with CSF1 levels, located in the vicinity of the CSF1 gene (cis), were used as instruments for CSF1 levels. Genetic association estimates for ischemic stroke and its subtypes, intra-cerebral hemorrhage (ICH), and cIMT were obtained from MEGASTROKE (60,341 cases and 454,450 controls), ISGC (1,545 cases and 1,481 controls), and UK Biobank (22,179 individuals), respectively. RESULTS: Genetically predicted higher CSF1 levels was significantly associated with a higher risk of any ischemic stroke, large artery stroke (LAS) and cardioembolic stroke (CES), but not with small vessel stroke (SVS) and ICH. The odds ratios (ORs) per genetically predicted one standard deviation (SD) increase in circulating CSF1 levels were 1.11 (95% CI 1.04-1.17) for any ischemic stroke, 1.23 (95% CI 1.07-1.42) for LAS, 1.18 (95% CI 1.05-1.33) for CES, 1.07 (95% CI 0.94-1.21) for SVS, and 1.15 (95% CI 0.73-1.83) for ICH. Similarly, we also found that genetically predicted higher CSF1 levels were associated with higher cIMT, as a measure of subclinical atherosclerosis (cIMT, β 0.016, 95% CI, 0.004-0.029). CONCLUSIONS: This study provides evidence that genetically predicted higher CSF1 levels was associated with higher risk of any ischemic stroke, LAS, and CES. Whether targeting CSF1 or its receptors can reduce the risk of ischemic stroke needs further study.
Kintu C, Soremekun O, Kamiza AB, et al., 2023, The causal effects of lipid traits on kidney function in Africans: bidirectional and multivariable Mendelian-randomization study., EBioMedicine, Vol: 90
BACKGROUND: Observational studies have investigated the effect of serum lipids on kidney function, but these findings are limited by confounding, reverse causation and have reported conflicting results. Mendelian randomization (MR) studies address this confounding problem. However, they have been conducted mostly in European ancestry individuals. We, therefore, set out to investigate the effect of lipid traits on the estimated glomerular filtration rate (eGFR) based on serum creatinine in individuals of African ancestry. METHODS: We used the two-sample and multivariable Mendelian randomization (MVMR) approaches; in which instrument variables (IV's) for the predictor (lipid traits) were derived from summary-level data of a meta-analyzed African lipid GWAS (MALG, n = 24,215) from the African Partnership for Chronic Disease Research (APCDR) (n = 13,612) & the Africa Wits-IN-DEPTH partnership for Genomics studies (AWI-Gen) dataset (n = 10,603). The outcome IV's were computed from the eGFR summary-level data of African-ancestry individuals within the Million Veteran Program (n = 57,336). A random-effects inverse variance method was used in our primary analysis, and pleiotropy was adjusted for using robust and penalized sensitivity testing. The lipid predictors for the MVMR were high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG). FINDINGS: We found a significant causal association between genetically predicted low-density lipoprotein (LDL) cholesterol and eGFR in African ancestry individuals β = 1.1 (95% CI [0.411-1.788]; p = 0.002). Similarly, total cholesterol (TC) showed a significant causal effect on eGFR β = 1.619 (95% CI [0.412-2.826]; p = 0.009). However, the IVW estimate showed that genetically predicted HDL-C β = -0.164, (95% CI = [-1.329 to 1.00]; p = 0.782), and TG β
Zhang Z, Wang M, Gill D, et al., 2023, Genetically Predicted Sleep Traits and Functional Outcome After Ischemic Stroke: A Mendelian Randomization Study., Neurology, Vol: 100, Pages: e1159-e1165
BACKGROUND AND OBJECTIVES: Sleep traits can have implications for ischemic stroke recovery in observational studies. The purpose of our present study was to explore the relationship between genetically predicted sleep traits and poststroke functional outcomes with Mendelian randomization (MR) method. METHODS: Instrumental variables for insomnia and sleep duration were adopted from genome-wide association studies data of European ancestry individuals. Summary data for functional outcome after ischemic stroke were retrieved from the Genetics of Ischemic Stroke Functional Outcome network. Inverse-variance weighted approach was adopted as the main analyses. Alternative MR approaches were used in sensitivity analyses. I2 and Q value statistics were used to appraise the heterogeneity among genetic variants. RESULTS: In univariable analysis, genetic liability to insomnia was significantly associated with worse functional outcome (modified Rankin Scale ≥3) after ischemic stroke (odds ratio [OR] = 1.30; 95% CI: 1.10-1.54, p = 0.002). Genetic liability to short sleep, long sleep, and continuous sleep duration were not associated with poststroke functional outcome (all p > 0.05). Sensitivity analyses without adjustment for stroke severity also supported that insomnia was causally associated with poor functional outcome (OR = 1.25; 95% CI: 1.08-1.44, p = 0.003). In the multivariable MR analysis adjusting for potentially confounding traits including body mass index, depression, type 2 diabetes, smoking, and alcohol consumption, the overall patterns between genetic liability to insomnia and poststroke outcome remained (all p < 0.05). DISCUSSION: This MR study supports potential adverse effects of liability to insomnia on functional outcome after ischemic stroke. Interventions that address insomnia may offer a therapeutic target to improve recovery after ischemic stroke and warrant exploration in a clinical context.
Yuan S, Wang L, Zhang H, et al., 2023, Mendelian randomization and clinical trial evidence supports TYK2 inhibition as a therapeutic target for autoimmune diseases, EBIOMEDICINE, Vol: 89, ISSN: 2352-3964
Chalitsios CV, Georgiou A, Bouras E, et al., 2023, Investigating modifiable pathways in psoriasis: A Mendelian randomization study., J Am Acad Dermatol, Vol: 88, Pages: 593-601
BACKGROUND: Potentially modifiable risk factors have previously been investigated only in conventional observational studies. OBJECTIVE: To assess whether genetically predicted exposures to modifiable factors are associated with the risk of psoriasis. METHODS: Two-sample Mendelian randomization (MR) analysis. RESULTS: An increased risk of psoriasis was noted for genetically predicted lifetime smoking index (odds ratio [OR]MR-IVW = 2.11; 95% confidence interval [CI], 1.28-3.51), childhood (OR MR-IVW = 1.40; 95% CI, 1.14-1.71) and adult body mass index (OR MR-IVW = 1.63; 95% CI, 1.32-2), waist (OR IVW = 1.86; 95% CI, 1.31-2.64), and hip circumference (OR MR-IVW = 1.55; 95% CI, 1.15-2.07). Protective association was also reported between genetically predicted longer sleep duration (OR MR-IVW = 0.56; 95% CI 0.37-0.84) and increased years of education (OR MR-IVW = 0.78; 95% CI, 0.62-0.98). This effect of education persisted in multivariable MR after adjusting for genetic predictors of smoking and adult body mass index (ORMVMR-IVW = 0.72; 95% CI, 0.56-0.92). LIMITATIONS: It was not possible to stratify for psoriasis severity. CONCLUSION: Smoking cessation and prevention of obesity are important strategies for decreasing the incidence of psoriasis. Similarly, targeting education inequality is expected to lead further to reductions in cases of psoriasis.
Huang J, Gill D, Zuber V, et al., 2023, Circulatory proteins relate cardiovascular disease to cognitive performance: a Mendelian randomisation study, Frontiers in Genetics, Vol: 14, Pages: 1-11, ISSN: 1664-8021
Background and objectives: Mechanistic research suggests synergistic effects of cardiovascular disease (CVD) and dementia pathologies on cognitive decline. Interventions targeting proteins relevant to shared mechanisms underlying CVD and dementia could also be used for the prevention of cognitive impairment.Methods: We applied Mendelian randomisation (MR) and colocalization analysis to investigate the causal relationships of 90 CVD-related proteins measured by the Olink CVD I panel with cognitive traits. Genetic instruments for circulatory protein concentrations were obtained using a meta-analysis of genome-wide association studies (GWAS) from the SCALLOP consortium (N = 17,747) based on three sets of criteria: 1) protein quantitative trait loci (pQTL); 2) cis-pQTL (pQTL within ±500 kb from the coding gene); and 3) brain-specific cis-expression QTL (cis-eQTL) which accounts for coding gene expression based on GTEx8. Genetic associations of cognitive performance were obtained from GWAS for either: 1) general cognitive function constructed using Principal Component Analysis (N = 300,486); or, 2) g Factor constructed using genomic structural equation modelling (N = 11,263–331,679). Findings for candidate causal proteins were replicated using a separate protein GWAS in Icelanders (N = 35,559).Results: A higher concentration of genetically predicted circulatory myeloperoxidase (MPO) was nominally associated with better cognitive performance (p < 0.05) using different selection criteria for genetic instruments. Particularly, brain-specific cis-eQTL predicted MPO, which accounts for protein-coding gene expression in brain tissues, was associated with general cognitive function (βWald = 0.22, PWald = 2.4 × 10−4). The posterior probability for colocalization (PP.H4) of MPO pQTL with the g Factor was 0.577. Findings for MPO were replicated using the Icelandic GWAS. Although we did not find evidence for colocalization, we found that higher gene
Huang J, Su B, Karhunen V, et al., 2023, Inflammatory diseases, inflammatory biomarkers, and Alzheimer disease: an observational analysis and mendelian randomization, Neurology, Vol: 100, Pages: e568-e581, ISSN: 0028-3878
OBJECTIVES: Whether chronic autoimmune inflammatory diseases causally affect the risk of AD is controversial. We characterised the relationship between inflammatory diseases and the risk of AD and explore the role of circulating inflammatory biomarkers in the relationships between inflammatory diseases and AD. METHODS: We performed observational analyses for chronic autoimmune inflammatory diseases and risk of AD using data from 2,047,513 participants identified in the UK Clinical Practice Research Datalink (CPRD). Using data of a total of more than 1,100,000 individuals from 15 large scale genome-wide association study (GWAS) datasets, we performed two-sample Mendelian randomisation (MR) to investigate the relationships between chronic autoimmune inflammatory diseases, circulating inflammatory biomarker levels, and risk of AD. RESULTS: Cox regression models using CPRD data showed that overall incidence of AD was higher among patients with inflammatory bowel disease (IBD) (hazard ratio (HR)=1.17; 95%CI 1.15 to 1.19; P-value=2.1×10-4), other inflammatory polyarthropathies & systematic connective tissue disorders (OID) (HR=1.13; 95%CI 1.12 to 1.14; P-value=8.6×10-5), psoriasis (HR=1.13; 95%CI 1.10 to 1.16; P-value=2.6×10-4), rheumatoid arthritis (RA) (HR=1.08; 95%CI 1.06 to 1.11; P-value=4.0×10-4), and multiple sclerosis (MS) (HR=1.06; 95%CI 1.04 to 1.07; P-value=2.8×10-4) compared to the age (± 5 years) and sex-matched comparison groups free from all inflammatory diseases under investigation. Bidirectional MR analysis identified relationships between chronic autoimmune inflammatory diseases and circulating inflammatory biomarkers. Particularly, circulating monokine induced by gamma interferon (MIG) level was suggestively associated with a higher risk of AD (odds ratio from inverse variance weighted (ORIVW)=1.23; 95%CI 1.06 to 1.42; PIVW=0.007), and lower risk of Crohn's disease (ORIVW=0.73; 95%CI -0.62, 0.86; PIVW=1.3×10
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.