scholarly journals Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

2021 ◽  
Author(s):  
Fernanda Morales-Berstein ◽  
Daniel L McCartney ◽  
Ake T Lu ◽  
Konstantinos K Tsilidis ◽  
Emmanouil Bouras ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Research ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Cancer Epidemiology ◽  
Sensitivity Analyses ◽  
Uk Biobank ◽  
University Of Bristol ◽  
The University ◽  
Programme Grant

ABSTRACTBackgroundEpigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.MethodsWe conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (9 single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs) and GrimAge (4 SNPs) on multiple cancers (i.e., breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N=34,710), and for cancer from the UK Biobank (N cases=2,671–13,879; N controls=173,493–372,016), FinnGen (N cases=719–8,401; N controls=74,685–174,006) and several international cancer genetic consortia (N cases=11,348–122,977; N controls=15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.ResultsMeta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR=1.12 per year increase in GrimAge acceleration, 95%CI 1.04–1.20, p=0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR=1.15, 95%CI 1.09–1.21, p=0.006), than rectal cancer (IVW OR=1.05, 95%CI 0.97–1.13, p=0.24). We also found evidence that higher GrimAge acceleration decreased the risk of prostate cancer (pooled IVW OR=0.93 per year increase in GrimAge acceleration, 95%CI 0.87–0.99, p=0.02). This was supported by MR sensitivity analyses, but did not replicate in MR analyses using data on parental history of prostate cancer in UK Biobank (IVW OR=1.00, 95%CI 0.96–1.04, p=1.00). Results were less consistent for associations between other epigenetic clocks and cancers.ConclusionsGrimAge acceleration may increase the risk of colorectal cancer. Additionally, there is more limited evidence that it may be protective against prostate cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.FundingFMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme “Competitiveness, Entrepreneurship & Innovation” (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019).RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.

scholarly journals Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian randomization study based on 79,148 prostate cancer cases and 61,106 controls

2019 ◽  
Author(s):  
Nabila Kazmi ◽  
Philip Haycock ◽  
Konstantinos Tsilidis ◽  
Brigid M. Lynch ◽  
Therese Truong ◽  
...  
Keyword(s):  
Physical Activity ◽  
Prostate Cancer ◽  
Risk Factors ◽  
Cancer Research ◽  
Cancer Risk ◽  
Serum Iron ◽  
Mendelian Randomization ◽  
Prostate Cancer Risk ◽  
Uk Biobank ◽  
Unsaturated Fat

SummaryBackgroundProstate cancer is the second most common male cancer worldwide, but there is substantial geographical variation suggesting a potential role for modifiable risk factors in prostate carcinogenesis.MethodsWe identified previously reported prostate cancer risk factors from the World Cancer Research Fund’s (WCRF) systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79,148 cases and 61,106 controls) or aggressive (15,167 cases and 58,308 controls) prostate cancer using Mendelian randomization (MR) based on genome wide association study (GWAS) summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7,844 prostate cancer cases and 204,001 controls).FindingsWCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms (SNPs). In MR analyses for overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical-activity, OR=0.49 (0.33-0.72; p=0.0003); serum iron, OR=0.92 (0.86-0.98; p=0.007); body mass index (BMI), OR=0.90 (0.84-0.97; p=0.003); and mono-unsaturated fat, OR=1.11 (1.02-1.20; p=0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive prostate cancer risk: OR=1.07 (1.01-1.15; p=0.03).InterpretationThe results for physical-activity, serum iron, BMI, mono-unsaturated fat and height are compatible with causality for prostate cancer but more research is needed to rule out violations of MR assumptions for some risk factors. The results suggest that interventions aimed at increasing physical activity may reduce prostate cancer risk, but the direction of effects of BMI, and iron are at odds with their effects on other diseases, so the overall public health impact of intervening on these need to be considered.FundingWorld Cancer Research Fund International (2015/1421), Cancer Research UK program grant (C18281/A19169), National Institute for Health Research, Bristol Biomedical Research Centre, and Victorian Cancer Agency (MCRF18005).

scholarly journals Causal effect of renal function on venous thromboembolism: a two-sample Mendelian randomization investigation

2021 ◽  
Author(s):  
Shuai Yuan ◽  
Maria Bruzelius ◽  
Susanna C. Larsson
Keyword(s):  
Renal Function ◽  
Venous Thromboembolism ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Genome Wide ◽  
Increased Risk ◽  
Mr Study

AbstractWhether renal function is causally associated with venous thromboembolism (VTE) is not yet fully elucidated. We conducted a two-sample Mendelian randomization (MR) study to determine the causal effect of renal function, measured as estimated glomerular filtration rate (eGFR), on VTE. Single-nucleotide polymorphisms associated with eGFR were selected as instrumental variables at the genome-wide significance level (p < 5 × 10−8) from a meta-analysis of 122 genome-wide association studies including up to 1,046,070 individuals. Summary-level data for VTE were obtained from the FinnGen consortium (6913 VTE cases and 169,986 non-cases) and UK Biobank study (4620 VTE cases and 356,574 non-cases). MR estimates were calculated using the random-effects inverse-variance weighted method and combined using fixed-effects meta-analysis. Genetically predicted decreased eGFR was significantly associated with an increased risk of VTE in both FinnGen and UK Biobank. For one-unit decrease in log-transformed eGFR, the odds ratios of VTE were 2.93 (95% confidence interval (CI) 1.25, 6.84) and 4.46 (95% CI 1.59, 12.5) when using data from FinnGen and UK Biobank, respectively. The combined odds ratio was 3.47 (95% CI 1.80, 6.68). Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected. This MR-study supported a casual role of impaired renal function in VTE.

scholarly journals Using a Two-Sample Mendelian Randomization Method in Assessing the Causal Relationships Between Human Blood Metabolites and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Zixian Wang ◽  
Shiyu Chen ◽  
Qian Zhu ◽  
Yonglin Wu ◽  
Guifeng Xu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Human Blood ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Blood Metabolites ◽  
Causal Relationships

Background: Heart failure (HF) is the main cause of morbidity and mortality worldwide, and metabolic dysfunction is an important factor related to HF pathogenesis and development. However, the causal effect of blood metabolites on HF remains unclear.Objectives: Our chief aim is to investigate the causal relationships between human blood metabolites and HF risk.Methods: We used an unbiased two-sample Mendelian randomization (MR) approach to assess the causal relationships between 486 human blood metabolites and HF risk. Exposure information was obtained from Sample 1, which is the largest metabolome-based genome-wide association study (mGWAS) data containing 7,824 Europeans. Outcome information was obtained from Sample 2, which is based on the results of a large-scale GWAS meta-analysis of HF and contains 47,309 cases and 930,014 controls of Europeans. The inverse variance weighted (IVW) model was used as the primary two-sample MR analysis method and followed the sensitivity analyses, including heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis.Results: We observed that 11 known metabolites were potentially related to the risk of HF after using the IVW method (P &lt; 0.05). After adding another four MR models and performing sensitivity analyses, we found a 1-SD increase in the xenobiotics 4-vinylphenol sulfate was associated with ~22% higher risk of HF (OR [95%CI], 1.22 [1.07–1.38]).Conclusions: We revealed that the 4-vinylphenol sulfate may nominally increase the risk of HF by 22% after using a two-sample MR approach. Our findings may provide novel insights into the pathogenesis underlying HF and novel strategies for HF prevention.

Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Yanjun Guo ◽  
Wonil Chung ◽  
Zhilei Shan ◽  
Liming Liang
Keyword(s):  
Cardiovascular Diseases ◽  
Genetic Correlation ◽  
Multiple Testing ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Uk Biobank ◽  
Increased Risk ◽  
The Uk ◽  
Cardiovascular Traits ◽  
Shared Genetic

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.

scholarly journals Appraising causal relationships of dietary, nutritional and physical-activity exposures with overall and aggressive prostate cancer: two-sample Mendelian-randomization study based on 79 148 prostate-cancer cases and 61 106 controls

2019 ◽  
Vol 49 (2) ◽  
pp. 587-596 ◽  
Author(s):  
Nabila Kazmi ◽  
Philip Haycock ◽  
Konstantinos Tsilidis ◽  
Brigid M Lynch ◽  
Therese Truong ◽  
...  
Keyword(s):  
Physical Activity ◽  
Prostate Cancer ◽  
Risk Factors ◽  
Cancer Risk ◽  
Serum Iron ◽  
Mendelian Randomization ◽  
Prostate Cancer Risk ◽  
Uk Biobank ◽  
Monounsaturated Fat ◽  
Aggressive Prostate Cancer

Abstract Background Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis. Methods We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)’s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls). Results WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33–0.72; P = 0.0003); serum iron, OR = 0.92 (0.86–0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84–0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02–1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01–1.15; P = 0.03). Conclusions The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.

scholarly journals Low lymphocyte count is a risk factor for Parkinsons disease

2020 ◽  
Author(s):  
Melanie Peta Jensen ◽  
Benjamin M Jacobs ◽  
Ruth Dobson ◽  
Sara Bandres-Ciga ◽  
Cornelis Blauwendraat ◽  
...  
Keyword(s):  
Lymphocyte Count ◽  
Mendelian Randomization ◽  
Causal Role ◽  
Sensitivity Analyses ◽  
Diagnostic Feature ◽  
Uk Biobank ◽  
Parkinsons Disease ◽  
Markers Of Inflammation ◽  
Incident Cases ◽  
Differential Counts

Importance: Biomarkers for the early detection of Parkinsons disease (PD) are needed. Patients with PD display differences in peripheral blood biomarkers of immune function, including leukocyte differential counts and C-reactive protein (CRP), compared to controls. These differences may be useful biomarkers to predict PD, and may shed light on PD pathogenesis. Objectives: To identify whether peripheral immune dysregulation is a pre-diagnostic feature of PD, and whether it plays a causal role. Design: Cross-sectional association analysis of the relationship between differential leukocyte count and other markers of acute inflammation at enrolment, and incident cases of PD in UK Biobank. We used Mendelian randomization to establish whether differences in leukocyte differential counts have a causal influence on risk of PD. Setting: UK Biobank; a population-based cohort with over 500,000 participants aged 40-69 recruited in the UK between 2006 and 2010. Participants: PD cases were defined as individuals with an ICD-10 coded diagnosis of PD. Cases were defined as incident if their age at diagnosis was greater than their age at recruitment to UKB. Controls were defined as individuals without a diagnosis of PD. After applying exclusion criteria for pre-existing health conditions that can influence blood counts, 507 incident PD cases and 328,280 controls were included in the analysis. Exposure: Blood cell markers (absolute and relative counts) and other markers of inflammation were obtained from blood tests of participants taken at the initial visit. Results: Lower lymphocyte count was associated with increased odds of incident PD (odds ratio [OR] 0.77, 95% confidence interval [CI] 0.65-0.90). There was weaker evidence of association between lower eosinophil and monocyte counts, lower CRP, and higher neutrophil counts on risk of incident PD. The association between lymphopenia and incident PD remained robust to sensitivity analyses. Mendelian randomization analyses suggested that the effect of low lymphocyte count on PD risk was causal (OR 0.91, 95% CI 0.85 - 0.99). Conclusions and relevance: In this large, prospective setting, lower lymphocyte count was associated with higher risk of subsequent PD diagnosis. Furthermore genetic evidence supported a causal role for lymphocyte count on PD risk.

scholarly journals Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009525
Author(s):  
Mark Gormley ◽  
James Yarmolinsky ◽  
Tom Dudding ◽  
Kimberley Burrows ◽  
Richard M. Martin ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Meta Analysis ◽  
Uk Biobank ◽  
Limited Evidence ◽  
Cholesterol Lowering ◽  
Increased Risk ◽  
Secondary Analyses

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10-05), with good concordance between GAME-ON and UK Biobank (I2 = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.

More than 80% of total knee replacements can last for 25 years

BMJ ◽  
2019 ◽  
pp. l5680 ◽  
Author(s):  
Rob Cook ◽  
Peter Davidson ◽  
Rosie Martin
Keyword(s):  
Meta Analysis ◽  
Case Series ◽  
National Registry ◽  
Research Centre ◽  
University Hospitals ◽  
Total Knee Replacements ◽  
Knee Replacements ◽  
Total Knee ◽  
University Of Bristol ◽  
The University

The studyEvans JT, Walker R, Evans W, Blom AW, Sayers A, Whitehouse MRHow long does a knee replacement last? A systematic review and meta-analysis of case series and national registry reports with more than 15 years of follow-up.Published on 16 February 2019 Lancet 2019;393:655-63This study was supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol.To read the full NIHR Signal, go to: https://discover.dc.nihr.ac.uk/content/signal-000776/more-than-80-of-total-knee-replacements-can-last-for-25-years

scholarly journals Childhood obesity and multiple sclerosis: A Mendelian randomization study

2021 ◽  
pp. 135245852110017
Author(s):  
Adil Harroud ◽  
Ruth E Mitchell ◽  
Tom G Richardson ◽  
John A Morris ◽  
Vincenzo Forgetta ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Childhood Obesity ◽  
Mendelian Randomization ◽  
Pubertal Timing ◽  
Association Studies ◽  
Sensitivity Analyses ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Increased Risk ◽  
Age At Puberty

Background: Higher childhood body mass index (BMI) has been associated with an increased risk of multiple sclerosis (MS). Objective: To evaluate whether childhood BMI has a causal influence on MS, and whether this putative effect is independent from early adult obesity and pubertal timing. Methods: We performed Mendelian randomization (MR) using summary genetic data on 14,802 MS cases and 26,703 controls. Large-scale genome-wide association studies provided estimates for BMI in childhood ( n = 47,541) and adulthood ( n = 322,154). In multivariable MR, we examined the direct effects of each timepoint and further adjusted for age at puberty. Findings were replicated using the UK Biobank ( n = 453,169). Results: Higher genetically predicted childhood BMI was associated with increased odds of MS (odds ratio (OR) = 1.26/SD BMI increase, 95% confidence interval (CI): 1.07–1.50). However, there was little evidence of a direct effect after adjusting for adult BMI (OR = 1.03, 95% CI: 0.70–1.53). Conversely, the effect of adult BMI persisted independent of childhood BMI (OR = 1.43; 95% CI: 1.01–2.03). The addition of age at puberty did not alter the findings. UK Biobank analyses showed consistent results. Sensitivity analyses provided no evidence of pleiotropy. Conclusion: Genetic evidence supports an association between childhood obesity and MS susceptibility, mediated by persistence of obesity into early adulthood but independent of pubertal timing.

scholarly journals Body mass index and height and risk of cutaneous melanoma: Mendelian randomization analyses

2020 ◽  
Vol 49 (4) ◽  
pp. 1236-1245 ◽  
Author(s):  
Jean Claude Dusingize ◽  
Catherine M Olsen ◽  
Jiyuan An ◽  
Nirmala Pandeya ◽  
Matthew H Law ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Positive Association ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Melanoma Risk ◽  
Lifestyle Risk Factors

Abstract Background Height and body mass index (BMI) have both been positively associated with melanoma risk, although findings for BMI have been less consistent than height. It remains unclear, however, whether these associations reflect causality or are due to residual confounding by environmental and lifestyle risk factors. We re-evaluated these associations using a two-sample Mendelian randomization (MR) approach. Methods We identified single nucleotide polymorphisms (SNPs) for BMI and height from separate genome-wide association study (GWAS) meta-analyses. We obtained melanoma SNPs from the most recent melanoma GWAS meta-analysis comprising 12 874 cases and 23 203 controls. We used the inverse variance-weighted estimator to derive separate causal risk estimates across all SNP instruments for BMI and height. Results Based on the combined estimate derived from 730 SNPs for BMI, we found no evidence of an association between genetically predicted BMI and melanoma [odds ratio (OR) per one standard deviation (1 SD) (4.6 kg/m2) increase in BMI 1.00, 95% confidence interval (CI): 0.91–1.11]. In contrast, we observed a positive association between genetically-predicted height (derived from a pooled estimate of 3290 SNPs) and melanoma risk [OR 1.08, 95% CI: 1.02–1.13, per 1 SD (9.27 cm) increase in height]. Sensitivity analyses using two alternative MR methods yielded similar results. Conclusions These findings provide no evidence for a causal association between higher BMI and melanoma, but support the notion that height is causally associated with melanoma risk. Mechanisms through which height influences melanoma risk remain unclear, and it remains possible that the effect could be mediated through diverse pathways including growth factors and even socioeconomic status.

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