Imperial College London

DrDipenderGill

Faculty of MedicineSchool of Public Health

Honorary Clinical Research Fellow
 
 
 
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Contact

 

+44 (0)7904 843 810dipender.gill

 
 
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Location

 

School of a Public HealthMedical SchoolSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
to

170 results found

Zuber V, Grinberg NF, Gill D, Manipur I, Slob EAW, Patel A, Wallace C, Burgess Set al., 2022, Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches., Am J Hum Genet, Vol: 109, Pages: 767-782

Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets.

Journal article

Korte N, Ilkan Z, Pearson CL, Pfeiffer T, Singhal P, Rock JR, Sethi H, Gill D, Attwell D, Tammaro Pet al., 2022, The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia., J Clin Invest, Vol: 132

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activated chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer's disease and vascular dementia.

Journal article

Yuan S, Chen J, Li X, Fan R, Arsenault B, Gill D, Giovannucci EL, Zheng J-S, Larsson SCet al., 2022, Lifestyle and metabolic factors for nonalcoholic fatty liver disease: Mendelian randomization study, EUROPEAN JOURNAL OF EPIDEMIOLOGY, ISSN: 0393-2990

Journal article

Larsson SC, Woolf B, Gill D, 2022, Plasma Caffeine Levels and Risk of Alzheimer's Disease and Parkinson's Disease: Mendelian Randomization Study., Nutrients, Vol: 14

We leveraged genetic variants associated with caffeine metabolism in the two-sample Mendelian randomization framework to investigate the effect of plasma caffeine levels on the risk of Alzheimer's disease and Parkinson's disease. Genetic association estimates for the outcomes were obtained from the International Genomics of Alzheimer's Project, the International Parkinson's Disease Genomics consortium, the FinnGen consortium, and the UK Biobank. Genetically predicted higher plasma caffeine levels were associated with a non-significant lower risk of Alzheimer's disease (odds ratio 0.87; 95% confidence interval 0.76, 1.00; p = 0.056). A suggestive association was observed for genetically predicted higher plasma caffeine levels and lower risk of Parkinson's disease in the FinnGen consortium. but not in the International Parkinson's Disease Genomics consortium; no overall association was found (odds ratio 0.92; 95% confidence interval 0.77, 1.10; p = 0.347). This study found possible suggestive evidence of a protective role of caffeine in Alzheimer's disease. The association between caffeine and Parkinson's disease requires further study.

Journal article

Soremekun O, Karhunen V, He Y, Rajasundaram S, Liu B, Gkatzionis A, Soremekun C, Udosen B, Musa H, Silva S, Kintu C, Mayanja R, Nakabuye M, Machipisa T, Mason A, Vujkovic M, Zuber V, Soliman M, Mugisha J, Nash O, Kaleebu P, Nyirenda M, Chikowore T, Nitsch D, Burgess S, Gill D, Fatumo Set al., 2022, Lipid traits and type 2 diabetes risk in African ancestry individuals: a Mendelian Randomization study, EBioMedicine, Vol: 78, ISSN: 2352-3964

BACKGROUND: Dyslipidaemia is highly prevalent in individuals with type 2 diabetes mellitus (T2DM). Numerous studies have sought to disentangle the causal relationship between dyslipidaemia and T2DM liability. However, conventional observational studies are vulnerable to confounding. Mendelian Randomization (MR) studies (which address this bias) on lipids and T2DM liability have focused on European ancestry individuals, with none to date having been performed in individuals of African ancestry. We therefore sought to use MR to investigate the causal effect of various lipid traits on T2DM liability in African ancestry individuals. METHODS: Using univariable and multivariable two-sample MR, we leveraged summary-level data for lipid traits and T2DM liability from the African Partnership for Chronic Disease Research (APCDR) (N = 13,612, 36.9% men) and from African ancestry individuals in the Million Veteran Program (Ncases = 23,305 and Ncontrols = 30,140, 87.2% men), respectively. Genetic instruments were thus selected from the APCDR after which they were clumped to obtain independent instruments. We used a random-effects inverse variance weighted method in our primary analysis, complementing this with additional sensitivity analyses robust to the presence of pleiotropy. FINDINGS: Increased genetically proxied low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were associated with increased T2DM liability in African ancestry individuals (odds ratio (OR) [95% confidence interval, P-value] per standard deviation (SD) increase in LDL-C = 1.052 [1.000 to 1.106, P = 0.046] and per SD increase in TC = 1.089 [1.014 to 1.170, P = 0.019]). Conversely, increased genetically proxied high-density lipoprotein cholesterol (HDL-C) was associated with reduced T2DM liability (OR per SD increase in HDL-C = 0.915 [0.843 to 0.993, P = 0.033]). The OR on T2DM per SD increase i

Journal article

Rogne T, Burgess S, Gill D, 2022, Systemic iron status and maternal pregnancy complications: a Mendelian randomization study, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, ISSN: 0300-5771

Journal article

Yuan S, Gill D, Giovannucci EL, Larsson SCet al., 2022, Obesity, type 2 diabetes, lifestyle factors, and risk of gallstone disease: a Mendelian randomization investigation, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: e529-e537, ISSN: 1542-3565

BACKGROUND & AIMS: Obesity, type 2 diabetes, and lifestyle factors (cigarette smoking, alcohol drinking, and coffee consumption) have been associated with the risk of developing gallstone disease in observational studies, but whether these associations are causal is undetermined. We conducted a Mendelian randomization study to assess these associations. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5×10-8) level were selected from corresponding genome-wide associations studies (n=224 459 to 1 232 091 individuals). Summary-level data for gallstone disease were obtained from the UK Biobank (10 520 cases and 350 674 non-cases) and FinnGen consortium (11 675 cases and 121 348 non-cases). Univariable and multivariable Mendelian randomization analyses were conducted. Results from UK Biobank and FinnGen were combined using fixed-effects meta-analysis. RESULTS: The odds ratios were 1.63 (95% confidence interval (CI), 1.49, 1.79) for one standard deviation (SD) increase in body mass index, 1.81 (95% CI, 1.60, 2.05) for one SD increase in waist circumference, 1.13 (95% CI, 1.09, 1.17) for one unit increase in the log-odds ratio of type 2 diabetes and 1.25 (95% CI, 1.16, 1.34) for one SD increase in prevalence of smoking initiation. The associations for body mass index and type 2 diabetes persisted after mutual adjustment. Genetically predicted coffee consumption was inversely associated with gallstone disease after adjustment for body mass index and smoking (odds ratio per 50% increase 0.44, 95% CI, 0.21, 0.91). There was no association with alcohol consumption. CONCLUSIONS: This study supports independent causal roles of obesity, type 2 diabetes, and smoking in gallstone disease.

Journal article

Chikowore T, Ekoru K, Vujkovi M, Gill D, Pirie F, Young E, Sandhu MS, McCarthy M, Rotimi C, Adeyemo A, Motala A, Fatumo Set al., 2022, Polygenic Prediction of Type 2 Diabetes in Africa., Diabetes Care, Vol: 45, Pages: 717-723

OBJECTIVE: Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American, European, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS: Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS: The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American-derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19-4.03; P = 2.79 × 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS: African American-derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.

Journal article

Yuan S, Wang L, Sun J, Yu L, Zhou X, Yang J, Zhu Y, Gill D, Burgess S, Denny JC, Larsson SC, Theodoratou E, Li Xet al., 2022, Genetically predicted sex hormone levels and health outcomes: phenome-wide Mendelian randomization investigation, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, ISSN: 0300-5771

Journal article

Zhao SS, Karhunen V, Morris AP, Gill Det al., 2022, ADAMTS5 as a therapeutic target for osteoarthritis: Mendelian randomisation study, ANNALS OF THE RHEUMATIC DISEASES, ISSN: 0003-4967

Journal article

Carter AR, Harrison S, Gill D, Davey Smith G, Taylor AE, Howe LD, Davies NMet al., 2022, Educational attainment as a modifier for the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank., Int J Epidemiol

BACKGROUND: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases. RESULTS: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk.

Journal article

Markozannes G, Kanellopoulou A, Dimopoulou O, Kosmidis D, Zhang X, Wang L, Theodoratou E, Gill D, Burgess S, Tsilidis KKet al., 2022, Systematic review of Mendelian randomization studies on risk of cancer, BMC Medicine, Vol: 20, ISSN: 1741-7015

BackgroundWe aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.MethodsWe searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.ResultsWe included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.ConclusionsDespite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.

Journal article

Cupido AJ, Kraaijenhof JM, Burgess S, Asselbergs FW, Hovingh GK, Gill Det al., 2022, Genetically Predicted Neutrophil-to-Lymphocyte Ratio and Coronary Artery Disease: Evidence From Mendelian Randomization, CIRCULATION-GENOMIC AND PRECISION MEDICINE, Vol: 15, ISSN: 2574-8300

Journal article

Gill D, Burgess S, 2022, The evolution of mendelian randomization for investigating drug effects, PLOS MEDICINE, Vol: 19, ISSN: 1549-1277

Journal article

Grant AJ, Gill D, Kirk PDW, Burgess Set al., 2022, Noise-augmented directional clustering of genetic association data identifies distinct mechanisms underlying obesity, PLoS Genetics, Vol: 18, ISSN: 1553-7390

Clustering genetic variants based on their associations with different traits can provide insight into their underlying biological mechanisms. Existing clustering approaches typically group variants based on the similarity of their association estimates for various traits. We present a new procedure for clustering variants based on their proportional associations with different traits, which is more reflective of the underlying mechanisms to which they relate. The method is based on a mixture model approach for directional clustering and includes a noise cluster that provides robustness to outliers. The procedure performs well across a range of simulation scenarios. In an applied setting, clustering genetic variants associated with body mass index generates groups reflective of distinct biological pathways. Mendelian randomization analyses support that the clusters vary in their effect on coronary heart disease, including one cluster that represents elevated body mass index with a favourable metabolic profile and reduced coronary heart disease risk. Analysis of the biological pathways underlying this cluster identifies inflammation as potentially explaining differences in the effects of increased body mass index on coronary heart disease.

Journal article

Taylor-Bateman V, Gill D, Georgakis M, Malik R, Munroe P, Traylor Met al., 2022, Cardiovascular Risk Factors and MRI Markers of Cerebral Small Vessel Disease A Mendelian Randomization Study, NEUROLOGY, Vol: 98, Pages: E343-E351, ISSN: 0028-3878

Journal article

Tsilidis K, 2022, Circulating inflammatory cytokines and risk of five cancers: a mendelian randomization analysis, BMC Medicine, Vol: 20, ISSN: 1741-7015

Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer etiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically-predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomization (MR) analysis.Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian and prostate) and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12 906 for endometrial to 133 384 for breast cancer). Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95%CI: 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85); and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer etiology. Further va

Journal article

Ardissino M, Slob E, Millar O, Reddy R, Lazzari L, Patel KHK, Ryan D, Johnson M, Gill D, Ng FSet al., 2022, Maternal hypertension increases risk of pre-eclampsia and low fetal birthweight: genetic evidence from a Mendelian randomization study, Hypertension, Vol: 79, Pages: 1-11, ISSN: 0194-911X

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing pre-eclampsia or eclampsia, and low fetal birthweight.Methods: Uncorrelated single nucleotide polymorphisms associated systolic blood pressure, body mass index, type 2 diabetes mellitus, low-density lipoprotein with cholesterol, smoking, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate at genome-wide significance in studies of 298,957 to 1,201,909 European ancestry participants were selected as instrumental variables. A two-sample Mendelian randomization study was performed with primary outcome of pre-eclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically-predicted systolic blood pressure was associated increased risk of PET [odds ratio (OR) per 1-SD systolic blood pressure increase 1.90 (95% confidence interval (CI)1.45-2.49;p=3.23x10-6 and reduced birthweight (OR=0.83; 95%CI=0.79-0.86;p=3.96x10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase=1.67 95%CI=1.44-1.94,;p=7.45x10-12; and OR per logOR increase type 2 diabetes=1.11 95%CI=1.04-1.19p;=1.19x10-3), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of systolic blood pressure, body mass index and type 2 diabetes on PET, and identify that systolic blood pressure is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Journal article

Ardissino M, Reddy RK, Slob EAW, Patel KHK, Ryan DK, Gill D, Ng FSet al., 2022, Sleep disordered breathing, obesity and atrial fibrillation: a mendelian randomisation study, Geneses, Vol: 13, Pages: 1-11, ISSN: 1155-3219

It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF. Single-nucleotide polymorphisms associated with SDB (n = 29) and BMI (n = 453) were selected as instrumental variables to investigate the effects of SDB and BMI on AF, using genetic association data on 55,114 AF cases and 482,295 controls. Primary analysis was conducted using inverse-variance weighted MR. Higher genetically predicted SDB and BMI were associated with increased risk of AF (OR per log OR increase in snoring liability 2.09 (95% CI 1.10–3.98), p = 0.03; OR per 1-SD increase in BMI 1.33 (95% CI 1.24–1.42), p < 0.001). The association between SDB and AF was not observed in sensitivity analyses, whilst associations between BMI and AF remained consistent. Similarly, in multivariable MR, SDB was not associated with AF after adjusting for BMI (OR 0.68 (95% CI 0.42–1.10), p = 0.12). Higher BMI remained associated with increased risk of AF after adjusting for OSA (OR 1.40 (95% CI 1.30–1.51), p < 0.001). Elevated BMI appears causal for AF, independent of SDB. Our data suggest that the association between SDB, in general, and AF is attributable to mediation or confounding from obesity, though we cannot exclude that more severe SDB phenotypes (i.e., OSA) are causal for AF.

Journal article

Rajasundaram S, Rahman RP, Woolf B, Zhao SS, Gill Det al., 2022, Morning Cortisol and Circulating Inflammatory Cytokine Levels: A Mendelian Randomisation Study, GENES, Vol: 13

Journal article

Wu P, Moon J-Y, Daghlas I, Franco G, Porneala BC, Ahmadizar F, Richardson TG, Isaksen JL, Hindy G, Yao J, Sitlani CM, Raffield LM, Yanek LR, Feitosa MF, Cuadrat RRC, Qi Q, Arfan Ikram M, Ellervik C, Ericson U, Goodarzi MO, Brody JA, Lange L, Mercader JM, Vaidya D, An P, Schulze MB, Masana L, Ghanbari M, Olesen MS, Cai J, Guo X, Floyd JS, Jäger S, Province MA, Kalyani RR, Psaty BM, Orho-Melander M, Ridker PM, Kanters JK, Uitterlinden A, Davey Smith G, Gill D, Kaplan RC, Kavousi M, Raghavan S, Chasman DI, Rotter JI, Meigs JB, Florez JC, Dupuis J, Liu C-T, Merino Jet al., 2022, Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol., Diabetes Care, Vol: 45, Pages: 232-240

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (β = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

Journal article

Burgess S, Gill D, 2021, Genetic evidence for vitamin D and cardiovascular disease: choice of variants is critical, EUROPEAN HEART JOURNAL, ISSN: 0195-668X

Journal article

Giontella A, Lotta L, Overton J, Baras A, Sartorio A, Minuz P, Gill D, Melander O, Fava Cet al., 2021, Association of thyroid function with blood pressure and cardiovascular disease: a mendelian randomization, Journal of Personalized Medicine, Vol: 11, Pages: 1-8, ISSN: 2075-4426

Thyroid function has a widespread effect on the cardiometabolic system. However, the causal association between either subclinical hyper- or hypothyroidism and the thyroid hormones with blood pressure (BP) and cardiovascular diseases (CVD) is not clear. We aim to investigate this in a two-sample Mendelian randomization (MR) study. Single nucleotide polymorphisms (SNPs) associated with thyroid-stimulating hormone (TSH), free tetraiodothyronine (FT4), hyper- and hypothyroidism, and anti-thyroid peroxidase antibodies (TPOAb), from genome-wide association studies (GWAS), were selected as MR instrumental variables. SNPs–outcome (BP, CVD) associations were evaluated in a large-scale cohort, the Malmö Diet and Cancer Study (n = 29,298). Causal estimates were computed by inverse-variance weighted (IVW), weighted median, and MR-Egger approaches. Genetically increased levels of TSH were associated with decreased systolic BP and with a lower risk of atrial fibrillation. Hyperthyroidism and TPOAb were associated with a lower risk of atrial fibrillation. Our data support a causal association between genetically decreased levels of TSH and both atrial fibrillation and systolic BP. The lack of significance after Bonferroni correction and the sensitivity analyses suggesting pleiotropy, should prompt us to be cautious in their interpretation. Nevertheless, these findings offer mechanistic insight into the etiology of CVD. Further work into the genes involved in thyroid functions and their relation to cardiovascular outcomes may highlight pathways for targeted intervention.

Journal article

Gill D, Burgess S, 2021, Distinguishing causation from genetic correlation in a Mendelian randomisation framework, EUROPEAN RESPIRATORY JOURNAL, Vol: 58, ISSN: 0903-1936

Journal article

Karhunen V, Bakker MK, Ruigrok YM, Gill D, Larsson SCet al., 2021, Modifiable risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage: a mendelian randomization study, Journal of the American Heart Association, Vol: 10, Pages: 1-19, ISSN: 2047-9980

BackgroundThe aim of this study was to assess the associations of modifiable lifestyle factors (smoking, coffee consumption, sleep, and physical activity) and cardiometabolic factors (body mass index, glycemic traits, type 2 diabetes, systolic and diastolic blood pressure, lipids, and inflammation and kidney function markers) with risks of any (ruptured or unruptured) intracranial aneurysm and aneurysmal subarachnoid hemorrhage using Mendelian randomization.Methods and ResultsSummary statistical data for the genetic associations with the modifiable risk factors and the outcomes were obtained from meta‐analyses of genome‐wide association studies. The inverse‐variance weighted method was used as the main Mendelian randomization analysis, with additional sensitivity analyses conducted using methods more robust to horizontal pleiotropy. Genetic predisposition to smoking, insomnia, and higher blood pressure was associated with an increased risk of both intracranial aneurysm and aneurysmal subarachnoid hemorrhage. For intracranial aneurysm, the odds ratios were 3.20 (95% CI, 1.93–5.29) per SD increase in smoking index, 1.24 (95% CI, 1.10–1.40) per unit increase in log‐odds of insomnia, and 2.92 (95% CI, 2.49–3.43) per 10 mm Hg increase in diastolic blood pressure. In addition, there was weak evidence for associations of genetically predicted decreased physical activity, higher triglyceride levels, higher body mass index, and lower low‐density lipoprotein cholesterol levels with higher risk of intracranial aneurysm and aneurysmal subarachnoid hemorrhage, with 95% CI overlapping the null for at least 1 of the outcomes. All results were consistent in sensitivity analyses.ConclusionsThis Mendelian randomization study suggests that smoking, insomnia, and high blood pressure are major risk factors for intracranial aneurysm and aneurysmal subarachnoid hemorrhage.

Journal article

Zuber V, Cameron A, Myserlis E, Bottle L, Fernandez-Cadenas I, Burgess S, Anderson C, Dawson J, Gill Det al., 2021, Leveraging genetic data to elucidate the relationship between Covid-19 and ischemic stroke, Journal of the American Heart Association, Vol: 10, Pages: 1-24, ISSN: 2047-9980

BackgroundThe relationship between coronavirus disease 2019 (Covid-19) and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and ResultsAnalyses primarily focused on critical Covid-19, defined as hospitalization with Covid-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical Covid-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both Covid-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical Covid-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical Covid-19 and ischemic stroke (rg=0.29, false discovery rate (FDR)=0.012), body mass index (rg=0.21, FDR=0.00002) and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical Covid-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical Covid-19 liability 1.03, 95% confidence interval 1.00-1.06, p-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical Covid-19.ConclusionsThese data support that liability to critica

Journal article

Liu B, Mason AM, Sun L, Di Angelantonio E, Gill D, Burgess Set al., 2021, Genetically predicted Type 2 diabetes mellitus liability, glycated hemoglobin and cardiovascular diseases: a wide-angled mendelian randomization study, Genes, Vol: 12, Pages: 1-8, ISSN: 2073-4425

(1) Aim: To investigate the causal effects of T2DM liability and glycated haemoglobin (HbA1c) levels on various cardiovascular disease outcomes, both in the general population and in non-diabetic individuals specifically. (2) Methods: We selected 243 variants as genetic instruments for T2DM liability and 536 variants for HbA1c. Linear Mendelian randomization analyses were performed to estimate the associations of genetically-predicted T2DM liability and HbA1c with 12 cardiovascular disease outcomes in 367,703 unrelated UK Biobank participants of European ancestries. We performed secondary analyses in participants without diabetes (HbA1c < 6.5% with no diagnosed diabetes), and in participants without diabetes or pre-diabetes (HbA1c < 5.7% with no diagnosed diabetes). (3) Results: Genetically-predicted T2DM liability was positively associated (p < 0.004, 0.05/12) with peripheral vascular disease, aortic valve stenosis, coronary artery disease, heart failure, ischaemic stroke, and any stroke. Genetically-predicted HbA1c was positively associated with coronary artery disease and any stroke. Mendelian randomization estimates generally shifted towards the null when excluding diabetic and pre-diabetic participants from analyses. (4) Conclusions: This genetic evidence supports causal effects of T2DM liability and HbA1c on a range of cardiovascular diseases, suggesting that improving glycaemic control could reduce cardiovascular risk in a general population, with greatest benefit in individuals with diabetes.

Journal article

Rahman RP, McEwan L, Ryan DK, Gill Det al., 2021, Leveraging genetic data to investigate the effects of interleukin-6 receptor signalling on levels of 40 circulating cytokines, BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Vol: 88, Pages: 1373-1378, ISSN: 0306-5251

Journal article

Vujkovic M, Ramdas S, Lorenz KM, Guo X, Darlay R, Cordell HJ, He J, Gindin Y, Chung C, Myers RP, Schneider CV, Park J, Lee K, Serper M, Carr RM, Kaplan DE, Haas M, MacLean M, Witschey W, Zhu X, Tcheandjieu C, Kember RL, Kranzler HR, Verma A, Giri A, Klarin DM, Sun YV, Huang J, Huffman J, Creasy KT, Hand NJ, Liu C-T, Long MT, Yao J, Li X, Budoff M, Tan J, Lin HJ, Chen Y-DI, Taylor K, Chang R-K, Krauss R, Vilarinho SM, Brancale J, Nielsen J, Locke AE, Verweij N, Jones MB, Baras A, Reddy KR, Neuschwander-Tetri BA, Schwimmer J, Sanyal AJ, Chalasani NP, Ryan KA, Mitchell BD, Gill D, Wells A, Manduchi E, Saiman Y, Mahmud N, Miller DR, Reaven PD, Phillips LS, Muralidhar S, DuVall SL, Lee JS, Assimes TL, Pyarajan S, Cho K, Edwards TL, Damrauer SM, Wilson PWF, Gaziano JM, O'Donnell CJ, Khera A, Grant S, Brown CD, Tsao P, Saleheen D, Lotta L, Bastarache L, Anstee QM, Daly AK, Meigs JB, Rotter JI, Lynch JA, Rader DJ, Voight BF, Chang K-Met al., 2021, A GENOME-WIDE ASSOCIATION STUDY OF CHRONIC ALT-BASED NAFLD IN THE MILLION VETERAN PROGRAM WITH HISTOLOGICAL AND RADIOLOGICAL VALIDATION, Publisher: WILEY, Pages: 6A-7A, ISSN: 0270-9139

Conference paper

Jiang T, Gill D, Butterworth A, Burgess Set al., 2021, Assessing the Impact of Winner's Curse on Mendelian Randomisation, Publisher: WILEY, Pages: 762-763, ISSN: 0741-0395

Conference paper

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