Publications by authors named "Rebecca C Richmond"

68 Publications

Mendelian Randomization: Concepts and Scope.

Cold Spring Harb Perspect Med 2021 Aug 23. Epub 2021 Aug 23.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, United Kingdom.

Mendelian randomization (MR) is a method of studying the causal effects of modifiable exposures (i.e., potential risk factors) on health, social, and economic outcomes using genetic variants associated with the specific exposures of interest. MR provides a more robust understanding of the influence of these exposures on outcomes because germline genetic variants are randomly inherited from parents to offspring and, as a result, should not be related to potential confounding factors that influence exposure-outcome associations. The genetic variant can therefore be used as a tool to link the proposed risk factor and outcome, and to estimate this effect with less confounding and bias than conventional epidemiological approaches. We describe the scope of MR, highlighting the range of applications being made possible as genetic data sets and resources become larger and more freely available. We outline the MR approach in detail, covering concepts, assumptions, and estimation methods. We cover some common misconceptions, provide strategies for overcoming violation of assumptions, and discuss future prospects for extending the clinical applicability, methodological innovations, robustness, and generalizability of MR findings.
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http://dx.doi.org/10.1101/cshperspect.a040501DOI Listing
August 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Workplace interventions that aim to improve employee health and well-being in male-dominated industries: a systematic review.

Occup Environ Med 2021 May 25. Epub 2021 May 25.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

The published evidence on whether workplace health and well-being interventions are as effective in male-dominated industries compared with mixed-gender environments has not been synthesised. We performed a systematic review of workplace interventions aimed at improving employee health and well-being in male-dominated industries. We searched Web of Knowledge, PubMed, Medline, Cochrane Database and Web of Science for articles describing workplace interventions in male-dominated industries that address employee health and well-being. The primary outcome was to determine the effectiveness of the intervention and the process evaluation (intervention delivery and adherence). To assess the quality of evidence, Cochrane Collaboration's Risk of Bias Tool was used. Due to the heterogeneity of reported outcomes, meta-analysis was performed for only some outcomes and a narrative synthesis with albatross plots was presented. After full-text screening, 35 studies met the eligibility criteria. Thirty-two studies delivered the intervention face-to-face, while two were delivered via internet and one using postal mail. Intervention adherence ranged from 50% to 97%, dependent on mode of delivery and industry. 17 studies were considered low risk of bias. Albatross plots indicated some evidence of positive associations, particularly for interventions focusing on musculoskeletal disorders. There was little evidence of intervention effect on body mass index and systolic or diastolic blood pressure. Limited to moderate evidence of beneficial effects was found for workplace health and well-being interventions conducted within male-dominated industries. Such interventions in the workplace can be effective, despite a different culture in male-dominated compared with mixed industries, but are dependent on delivery, industry and outcome. CRD42019161283.
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http://dx.doi.org/10.1136/oemed-2020-107314DOI Listing
May 2021

Mendelian randomisation for mediation analysis: current methods and challenges for implementation.

Eur J Epidemiol 2021 May 7;36(5):465-478. Epub 2021 May 7.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Mediation analysis seeks to explain the pathway(s) through which an exposure affects an outcome. Traditional, non-instrumental variable methods for mediation analysis experience a number of methodological difficulties, including bias due to confounding between an exposure, mediator and outcome and measurement error. Mendelian randomisation (MR) can be used to improve causal inference for mediation analysis. We describe two approaches that can be used for estimating mediation analysis with MR: multivariable MR (MVMR) and two-step MR. We outline the approaches and provide code to demonstrate how they can be used in mediation analysis. We review issues that can affect analyses, including confounding, measurement error, weak instrument bias, interactions between exposures and mediators and analysis of multiple mediators. Description of the methods is supplemented by simulated and real data examples. Although MR relies on large sample sizes and strong assumptions, such as having strong instruments and no horizontally pleiotropic pathways, our simulations demonstrate that these methods are unaffected by confounders of the exposure or mediator and the outcome and non-differential measurement error of the exposure or mediator. Both MVMR and two-step MR can be implemented in both individual-level MR and summary data MR. MR mediation methods require different assumptions to be made, compared with non-instrumental variable mediation methods. Where these assumptions are more plausible, MR can be used to improve causal inference in mediation analysis.
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http://dx.doi.org/10.1007/s10654-021-00757-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159796PMC
May 2021

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

PLoS Genet 2021 04 22;17(4):e1009525. Epub 2021 Apr 22.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pgen.1009525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096036PMC
April 2021

Correction to: Letter regarding, "Association between the use of aspirin and risk of lung cancer: results from pooled cohorts and Mendelian randomization analyses".

J Cancer Res Clin Oncol 2021 Jul;147(7):2175

Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.

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http://dx.doi.org/10.1007/s00432-021-03636-0DOI Listing
July 2021

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 Mar 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021

Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT study.

Int J Epidemiol 2021 Mar 17. Epub 2021 Mar 17.

Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.

Background: It is unclear if smoking-related DNA methylation represents a causal pathway between smoking and risk of lung cancer. We sought to identify novel smoking-related DNA methylation sites in blood, with repeated measurements, and to appraise the putative role of DNA methylation in the pathway between smoking and lung cancer development.

Methods: We derived a nested case-control study from the Trøndelag Health Study (HUNT), including 140 incident patients who developed lung cancer during 2009-13 and 140 controls. We profiled 850 K DNA methylation sites (Illumina Infinium EPIC array) in DNA extracted from blood that was collected in HUNT2 (1995-97) and HUNT3 (2006-08) for the same individuals. Epigenome-wide association studies (EWAS) were performed for a detailed smoking phenotype and for lung cancer. Two-step Mendelian randomization (MR) analyses were performed to assess the potential causal effect of smoking on DNA methylation as well as of DNA methylation (13 sites as putative mediators) on risk of lung cancer.

Results: The EWAS for smoking in HUNT2 identified associations at 76 DNA methylation sites (P < 5 × 10-8), including 16 novel sites. Smoking was associated with DNA hypomethylation in a dose-response relationship among 83% of the 76 sites, which was confirmed by analyses using repeated measurements from blood that was collected at 11 years apart for the same individuals. Two-step MR analyses showed evidence for a causal effect of smoking on DNA methylation but no evidence for a causal link between DNA methylation and the risk of lung cancer.

Conclusions: DNA methylation modifications in blood did not seem to represent a causal pathway linking smoking and the lung cancer risk.
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http://dx.doi.org/10.1093/ije/dyab044DOI Listing
March 2021

Selection into shift work is influenced by educational attainment and body mass index: a Mendelian randomization study in the UK Biobank.

Int J Epidemiol 2021 Aug;50(4):1229-1240

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Background: Shift work is associated with increased cardiometabolic disease risk. This observation may be partly explained by cardiometabolic risk factors having a role in the selection of individuals into or out of shift work. We performed Mendelian randomization (MR) analyses in the UK Biobank (UKB) to test this hypothesis.

Methods: We used genetic risk scores (GRS) to proxy nine cardiometabolic risk factors and diseases (including educational attainment, body mass index (BMI), smoking, and alcohol consumption), and tested associations of each GRS with self-reported frequency of current shift work among employed UKB participants of European ancestry (n = 190 573). We used summary-level MR sensitivity analyses to assess robustness of the identified effects, and we tested whether effects were mediated through sleep timing preference.

Results: Genetically instrumented liability to lower educational attainment (odds ratio (OR) per 3.6 fewer years in educational attainment = 2.40, 95% confidence interval (CI) = 2.22-2.59, P = 4.84 × 10-20) and higher body mass index (OR per 4.7 kg/m2 higher BMI = 1.30, 95% CI = 1.14-1.47, P = 5.85 × 10-5) increased odds of reporting participation in frequent shift work. Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy. No selection effects were evident for the remaining exposures, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate the effects of BMI and educational attainment on selection into shift work.

Conclusions: Liability to lower educational attainment and higher BMI may influence selection into shift work. This phenomenon may bias epidemiological studies of shift work that are performed in the UKB.
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http://dx.doi.org/10.1093/ije/dyab031DOI Listing
August 2021

Multi-omics analyses of cognitive traits and psychiatric disorders highlights brain-dependent mechanisms.

Hum Mol Genet 2021 Jan 22. Epub 2021 Jan 22.

MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.

Integrating findings from genome-wide association studies with molecular datasets can develop insight into the underlying functional mechanisms responsible for trait-associated genetic variants. We have applied the principles of Mendelian randomization (MR) to investigate whether brain-derived gene expression (n = 1194) may be responsible for mediating the effect of genetic variants on eight cognitive and psychological outcomes (attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, bipolar disorder, depression, intelligence, insomnia, neuroticism and schizophrenia). Transcriptome-wide analyses identified 83 genes associated with at least one outcome (PBonferroni < 6.72 × 10-6), with multiple-trait colocalization also implicating changes to brain-derived DNA methylation at nine of these loci. Comparing effects between outcomes identified evidence of enrichment which may reflect putative causal relationships, such as an inverse relationship between genetic liability towards schizophrenia risk and cognitive ability in later life. Repeating these analyses in whole blood (n = 31 684), we replicated 58.2% of brain-derived effects (based on P < 0.05). Finally, we undertook phenome-wide evaluations at associated loci to investigate pleiotropic effects with 700 complex traits. This highlighted pleiotropic loci such as FURIN (initially implicated in schizophrenia risk (P = 1.05 × 10-7)) which had evidence of an effect on 28 other outcomes, as well as genes which may have a more specific role in disease pathogenesis (e.g. SLC12A5 which only provided evidence of an effect on depression (P = 7.13 × 10-10)). Our results support the utility of whole blood as a valuable proxy for informing initial target identification but also suggest that gene discovery in a tissue-specific manner may be more informative. Finally, non-pleiotropic loci highlighted by our study may be of use for therapeutic translational endeavours.
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http://dx.doi.org/10.1093/hmg/ddab016DOI Listing
January 2021

Letter regarding, "Association between the use of aspirin and risk of lung cancer: results from pooled cohorts and Mendelian randomization analyses".

J Cancer Res Clin Oncol 2021 07 12;147(7):2171-2173. Epub 2021 Jan 12.

Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, BS8 2BN, UK.

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http://dx.doi.org/10.1007/s00432-020-03508-zDOI Listing
July 2021

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2021 03 14;30(3):564-575. Epub 2020 Dec 14.

Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL ( = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium ( = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively).

Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086774PMC
March 2021

A multivariable Mendelian randomization analysis investigating smoking and alcohol consumption in oral and oropharyngeal cancer.

Nat Commun 2020 11 27;11(1):6071. Epub 2020 Nov 27.

MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, BS8 1TL, UK.

The independent effects of smoking and alcohol in head and neck cancer are not clear, given the strong association between these risk factors. Their apparent synergistic effect reported in previous observational studies may also underestimate independent effects. Here we report multivariable Mendelian randomization performed in a two-sample approach using summary data on 6,034 oral/oropharyngeal cases and 6,585 controls from a recent genome-wide association study. Our results demonstrate strong evidence for an independent causal effect of smoking on oral/oropharyngeal cancer (IVW OR 2.6, 95% CI = 1.7, 3.9 per standard deviation increase in lifetime smoking behaviour) and an independent causal effect of alcohol consumption when controlling for smoking (IVW OR 2.1, 95% CI = 1.1, 3.8 per standard deviation increase in drinks consumed per week). This suggests the possibility that the causal effect of alcohol may have been underestimated. However, the extent to which alcohol is modified by smoking requires further investigation.
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http://dx.doi.org/10.1038/s41467-020-19822-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695733PMC
November 2020

The Role of Gallstones in Gallbladder Cancer in India: A Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 02 13;30(2):396-403. Epub 2020 Nov 13.

Centre for Cancer Epidemiology, Tata Memorial Centre, Kharghar, Navi Mumbai, Maharashtra, India.

Background: Past history of gallstones is associated with increased risk of gallbladder cancer in observational studies. We conducted complementary observational and Mendelian randomization (MR) analyses to determine whether history of gallstones is causally related to development of gallbladder cancer in an Indian population.

Methods: To investigate associations between history of gallstones and gallbladder cancer, we used questionnaire and imaging data from a gallbladder cancer case-control study conducted at Tata Memorial Hospital, Mumbai, Maharashtra, India (cases = 1,170; controls = 2,525). We then used 26 genetic variants identified in a genome-wide association study of 27,174 gallstone cases and 736,838 controls of European ancestry in an MR approach to assess causality. The association of these genetic variants with both gallstones and gallbladder cancer was examined in the gallbladder cancer case-control study. Various complementary MR approaches were used to evaluate the robustness of our results in the presence of pleiotropy and heterogeneity, and to consider the suitability of the selected SNPs as genetic instruments for gallstones in an Indian population.

Results: We found a strong observational association between gallstones and gallbladder cancer using self-reported history of gallstones [OR = 4.5; 95% confidence interval (CI) = 3.5-5.8] and with objective measures of gallstone presence using imaging techniques (OR = 2.0; 95% CI = 1.5-2.7). We found consistent causal estimates across all MR techniques, with ORs for gallbladder cancer in the range of 1.3-1.6.

Conclusions: Our findings indicate a causal relationship between history of gallstones and increased risk of gallbladder cancer, albeit of a smaller magnitude than those found in observational analysis.

Impact: Our findings emphasize the importance of gallstone treatment for preventing gallbladder cancer in high-risk individuals.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611244PMC
February 2021

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

Int J Epidemiol 2021 07;50(3):817-828

MRC Integrative Epidemiology Unit, at the University of Bristol, Bristol, UK.

Background: It is established that Alzheimer's disease (AD) patients experience sleep disruption. However, it remains unknown whether disruption in the quantity, quality or timing of sleep is a risk factor for the onset of AD.

Methods: We used the largest published genome-wide association studies of self-reported and accelerometer-measured sleep traits (chronotype, duration, fragmentation, insomnia, daytime napping and daytime sleepiness), and AD. Mendelian randomization (MR) was used to estimate the causal effect of self-reported and accelerometer-measured sleep parameters on AD risk.

Results: Overall, there was little evidence to support a causal effect of sleep traits on AD risk. There was some suggestive evidence that self-reported daytime napping was associated with lower AD risk [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.50-0.99). Some other sleep traits (accelerometer-measured 'eveningness' and sleep duration, and self-reported daytime sleepiness) had ORs of a similar magnitude to daytime napping, but were less precisely estimated.

Conclusions: Overall, we found very limited evidence to support a causal effect of sleep traits on AD risk. Our findings provide tentative evidence that daytime napping may reduce AD risk. Given that this is the first MR study of multiple self-report and objective sleep traits on AD risk, findings should be replicated using independent samples when such data become available.
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http://dx.doi.org/10.1093/ije/dyaa183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271193PMC
July 2021

DNA methylation signature of passive smoke exposure is less pronounced than active smoking: The Understanding Society study.

Environ Res 2020 11 31;190:109971. Epub 2020 Jul 31.

Population Health Sciences, Bristol Medical School, University of Bristol, BS8 2BN, UK; MRC Integrative Epidemiology Unit at University of Bristol, BS8 2BN, UK. Electronic address:

Introduction: The extent of the biological impact of passive smoke exposure is unclear. We sought to investigate the association between passive smoke exposure and DNA methylation, which could serve as a biomarker of health risk.

Materials And Methods: We derived passive smoke exposure from self-reported questionnaire data among smoking and non-smoking partners of participants enrolled in the UK Household Longitudinal Study 'Understanding Society' (n=769). We performed an epigenome-wide association study (EWAS) of passive smoke exposure with DNA methylation in peripheral blood measured using the Illumina Infinium Methylation EPIC array.

Results: No CpG sites surpassed the epigenome-wide significance threshold of p<5.97 × 10 in relation to partner smoking, compared with 10 CpG sites identified in relation to own smoking. However, 10 CpG sites surpassed a less stringent threshold of p<1 × 10 in a model of partner smoking adjusted for own smoking (model 1), 7 CpG sites in a model of partner smoking restricted to non-smokers (model 2) and 16 CpGs in a model restricted to regular smokers (model 3). In addition, there was evidence for an interaction between own smoking status and partners' smoking status on DNA methylation levels at the majority of CpG sites identified in models 2 and 3. There was a clear lack of enrichment for previously identified smoking signals in the EWAS of passive smoke exposure compared with the EWAS of own smoking.

Conclusion: The DNA methylation signature associated with passive smoke exposure is much less pronounced than that of own smoking, with no positive findings for 'expected' signals. It is unlikely that changes to DNA methylation serve as an important mechanism underlying the health risks of passive smoke exposure.
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http://dx.doi.org/10.1016/j.envres.2020.109971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536273PMC
November 2020

Investigating the added value of biomarkers compared with self-reported smoking in predicting future e-cigarette use: Evidence from a longitudinal UK cohort study.

PLoS One 2020 14;15(7):e0235629. Epub 2020 Jul 14.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.

Biomarkers can be used to assess smoking behaviour more accurately and objectively than self-report. This study assessed the association between cotinine (a biomarker of smoke exposure) and later e-cigarette use among a population who were unexposed to e-cigarettes in youth. Young people in the Avon Longitudinal Study of Parents and Children took part in the study. We observed associations between cotinine at 15 years (measured between 2006 and 2008 before the wide availability of e-cigarettes) and self-reported ever use of e-cigarettes at 22 (measured between 2014 and 2015 when e-cigarettes were widely available) using logistic regression. A range of potential confounders were adjusted for (age, sex, body mass index, alcohol use and passive smoke exposure). Additionally, we adjusted for the young people's self-reported smoking status/history to explore potential misreporting and measurement error. In a sample of N = 1,194 young people, cotinine levels consistent with active smoking at 15 years were associated with increased odds of e-cigarette ever use at 22 years (Odds Ratio [OR] = 7.24, 95% CI 3.29 to 15.93) even when self-reported active smoking status at age 16 (OR = 3.14, 95% CI 1.32 to 7.48) and latent classes of smoking behaviour from 14 to 16 (OR = 2.70, 95% CI 0.98 to 7.44) were included in the model. Cotinine levels consistent with smoking in adolescence were strongly associated with increased odds of later e-cigarette use, even after adjusting for reported smoking behaviour at age 16 and smoking transitions from 14 to 16.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360042PMC
September 2020

Epigenetic prediction of complex traits and mortality in a cohort of individuals with oropharyngeal cancer.

Clin Epigenetics 2020 04 22;12(1):58. Epub 2020 Apr 22.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Background: DNA methylation (DNAm) variation is an established predictor for several traits. In the context of oropharyngeal cancer (OPC), where 5-year survival is ~ 65%, DNA methylation may act as a prognostic biomarker. We examined the accuracy of DNA methylation biomarkers of 4 complex exposure traits (alcohol consumption, body mass index [BMI], educational attainment and smoking status) in predicting all-cause mortality in people with OPC.

Results: DNAm predictors of alcohol consumption, BMI, educational attainment and smoking status were applied to 364 individuals with OPC in the Head and Neck 5000 cohort (HN5000; 19.6% of total OPC cases in the study), followed up for median 3.9 years; inter-quartile range (IQR) 3.3 to 5.2 years (time-to-event-death or censor). The proportion of phenotypic variance explained in each trait was as follows: 16.5% for alcohol consumption, 22.7% for BMI, 0.4% for educational attainment and 51.1% for smoking. We then assessed the relationship between each DNAm predictor and all-cause mortality using Cox proportional-hazard regression analysis. DNAm prediction of smoking was most consistently associated with mortality risk (hazard ratio [HR], 1.38 per standard deviation (SD) increase in smoking DNAm score; 95% confidence interval [CI] 1.04 to 1.83; P 0.025, in a model adjusted for demographic, lifestyle, health and biological variables). Finally, we examined the accuracy of each DNAm predictor of mortality. DNAm predictors explained similar levels of variance in mortality to self-reported phenotypes. Receiver operator characteristic (ROC) curves for the DNAm predictors showed a moderate discrimination of alcohol consumption (area under the curve [AUC] 0.63), BMI (AUC 0.61) and smoking (AUC 0.70) when predicting mortality. The DNAm predictor for education showed poor discrimination (AUC 0.57). Z tests comparing AUCs between self-reported phenotype ROC curves and DNAm score ROC curves did not show evidence for difference between the two (alcohol consumption P 0.41, BMI P 0.62, educational attainment P 0.49, smoking P 0.19).

Conclusions: In the context of a clinical cohort of individuals with OPC, DNAm predictors for smoking, alcohol consumption, educational attainment and BMI exhibit similar predictive values for all-cause mortality compared to self-reported data. These findings may have translational utility in prognostic model development, particularly where phenotypic data are not available.
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http://dx.doi.org/10.1186/s13148-020-00850-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178612PMC
April 2020

Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways.

Am J Hum Genet 2020 03 20;106(3):315-326. Epub 2020 Feb 20.

Medical Research Council Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Electronic address:

Whether smoking-associated DNA methylation has a causal effect on lung function has not been thoroughly evaluated. We first investigated the causal effects of 474 smoking-associated CpGs on forced expiratory volume in 1 s (FEV) in UK Biobank (n = 321,047) by using two-sample Mendelian randomization (MR) and then replicated this investigation in the SpiroMeta Consortium (n = 79,055). Second, we used two-step MR to investigate whether DNA methylation mediates the effect of smoking on FEV. Lastly, we evaluated the presence of horizontal pleiotropy and assessed whether there is any evidence for shared causal genetic variants between lung function, DNA methylation, and gene expression by using a multiple-trait colocalization ("moloc") framework. We found evidence of a possible causal effect for DNA methylation on FEV at 18 CpGs (p < 1.2 × 10). Replication analysis supported a causal effect at three CpGs (cg21201401 [LIME1 and ZGPAT], cg19758448 [PGAP3], and cg12616487 [EML3 and AHNAK] [p < 0.0028]). DNA methylation did not clearly mediate the effect of smoking on FEV, although DNA methylation at some sites might influence lung function via effects on smoking. By using "moloc", we found evidence of shared causal variants between lung function, gene expression, and DNA methylation. These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results.
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http://dx.doi.org/10.1016/j.ajhg.2020.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058834PMC
March 2020

Mixed evidence for the relationship between periodontitis and Alzheimer's disease: A bidirectional Mendelian randomization study.

PLoS One 2020 24;15(1):e0228206. Epub 2020 Jan 24.

Department of Public Health and Nursing, NTNU-Norwegian University of Science and Technology, Trondheim, Norway.

Recent experimental studies indicated that a periodontitis-causing bacterium might be a causal factor for Alzheimer's disease (AD). We applied a two-sample Mendelian randomization (MR) approach to examine the potential causal relationship between chronic periodontitis and AD bidirectionally in the population of European ancestry. We used publicly available data of genome-wide association studies (GWAS) on periodontitis and AD. Five single-nucleotide polymorphisms (SNPs) were used as instrumental variables for periodontitis. For the MR analysis of periodontitis on risk of AD, the causal odds ratio (OR) and 95% confidence interval (CI) were derived from the GWAS of periodontitis (4,924 cases vs. 7,301 controls) and from the GWAS of AD (21,982 cases vs. 41,944 controls). Seven non-overlapping SNPs from another latest GWAS of periodontitis was used to validate the above association. Twenty SNPs were used as instrumental variables for AD. For the MR analysis of liability to AD on risk of periodontitis, the causal OR was derived from the GWAS of AD including 30,344 cases and 52,427 controls and from the GWAS of periodontitis consisted of 12,289 cases and 22,326 controls. We employed multiple methods of MR. Using the five SNPs as instruments of periodontitis, there was suggestive evidence of genetically predicted periodontitis being associated with a higher risk of AD (OR 1.10, 95% CI 1.02 to 1.19, P = 0.02). However, this association was not verified using the seven independent SNPs (OR 0.97, 95% CI 0.87 to 1.08, P = 0.59). There was no association of genetically predicted AD with the risk of periodontitis (OR 1.00, 95% CI 0.96 to 1.04, P = 0.85). In summary, we did not find convincing evidence to support periodontitis being a causal factor for the development of AD. There was also limited evidence to suggest genetic liability to AD being associated with the risk of periodontitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980529PMC
April 2020

A systematic review protocol examining workplace interventions that aim to improve employee health and wellbeing in male-dominated industries.

Syst Rev 2020 01 9;9(1):10. Epub 2020 Jan 9.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Background: The workplace environment potentially provides access to a large population who are employed, and it is an employer's responsibility to provide appropriate conditions for its employees. Whilst the aetiology of cardiovascular disease is multifactorial, it is generally acknowledged that working conditions, gender and age are involved in its development. Male-dominated industries (comprising > 70% male workers, e.g., agriculture, construction, manufacturing, mining, transport and technology) have a higher prevalence of health risk behaviours than other population subgroups. Working in a gender-dominated industry can impact an employee's health and wellbeing, particularly for the opposite sex. This systematic review examines workplace interventions that address the health and wellbeing of employees in male-dominated industries.

Methods: We will include randomised controlled trials and studies with non-randomised intervention groups. The interventions must aim to improve employee physical and/or mental health and wellbeing implemented in the workplace in male-dominated industries. There will be no limits on date. The following electronic databases will be searched for published studies: Web of Science, Embed, MedLine, PsycInfo and the Cochrane Database. The search strategy will include free-text terms and MeSH vocabulary, including 'male-dominated industries', 'workplace interventions', 'occupational stress', 'mental health', 'cardiovascular disease', 'blood pressure', 'body mass index' and 'exercise'. Two authors will independently select, review and extract data from studies that meet the inclusion criteria. The Cochrane's Risk of Bias tool will be used to assess risk of bias. We will perform structured summaries of the included studies and, if possible, conduct meta-analyses or construct an Albatross plot.

Discussion: There are an increasing number of interventions designed to improve employee health and wellbeing in the workplace, but no prior review that systematically evaluates their effectiveness. A systematic review is required to prioritise the future implementation of those interventions found to be most effective.

Systematic Review Registration: PROSPERO CRD42019161283.
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http://dx.doi.org/10.1186/s13643-019-1260-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953289PMC
January 2020

Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study.

Psychol Med 2020 10 6;50(14):2435-2443. Epub 2019 Nov 6.

School of Experimental Psychology, University of Bristol, BristolBS8 1TU, UK.

Background: Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).

Methods: We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium.

Results: There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67-3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71-2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027-0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005-0.038, p = 0.009) with very weak evidence for an effect on smoking initiation.

Conclusions: These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.
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http://dx.doi.org/10.1017/S0033291719002678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610182PMC
October 2020

Appraising the causal relevance of DNA methylation for risk of lung cancer.

Int J Epidemiol 2019 10;48(5):1493-1504

MRC Integrative Epidemiology Unit.

Background: DNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.

Methods: We first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.

Results: Sixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.

Conclusions: The results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.
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http://dx.doi.org/10.1093/ije/dyz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857764PMC
October 2019

Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.

Epigenomics 2019 10 19;11(13):1487-1500. Epub 2019 Sep 19.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for exposure in newborns is unknown. We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.
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http://dx.doi.org/10.2217/epi-2019-0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836223PMC
October 2019

Genome-wide association analysis of self-reported daytime sleepiness identifies 42 loci that suggest biological subtypes.

Nat Commun 2019 08 13;10(1):3503. Epub 2019 Aug 13.

Institute for Molecular Medicine FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.

Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with substantial functional deficits. Here, we identify 42 loci for self-reported daytime sleepiness in GWAS of 452,071 individuals from the UK Biobank, with enrichment for genes expressed in brain tissues and in neuronal transmission pathways. We confirm the aggregate effect of a genetic risk score of 42 SNPs on daytime sleepiness in independent Scandinavian cohorts and on other sleep disorders (restless legs syndrome, insomnia) and sleep traits (duration, chronotype, accelerometer-derived sleep efficiency and daytime naps or inactivity). However, individual daytime sleepiness signals vary in their associations with objective short vs long sleep, and with markers of sleep continuity. The 42 sleepiness variants primarily cluster into two predominant composite biological subtypes - sleep propensity and sleep fragmentation. Shared genetic links are also seen with obesity, coronary heart disease, psychiatric diseases, cognitive traits and reproductive ageing.
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http://dx.doi.org/10.1038/s41467-019-11456-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692391PMC
August 2019

A Phenome-Wide Mendelian Randomization Study of Pancreatic Cancer Using Summary Genetic Data.

Cancer Epidemiol Biomarkers Prev 2019 12 17;28(12):2070-2078. Epub 2019 Jul 17.

MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom.

Background: The 5-year mortality rate for pancreatic cancer is among the highest of all cancers. Greater understanding of underlying causes could inform population-wide intervention strategies for prevention. Summary genetic data from genome-wide association studies (GWAS) have become available for thousands of phenotypes. These data can be exploited in Mendelian randomization (MR) phenome-wide association studies (PheWAS) to efficiently screen the phenome for potential determinants of disease risk.

Methods: We conducted an MR-PheWAS of pancreatic cancer using 486 phenotypes, proxied by 9,124 genetic variants, and summary genetic data from a GWAS of pancreatic cancer (7,110 cancer cases, 7,264 controls). ORs and 95% confidence intervals per 1 SD increase in each phenotype were generated.

Results: We found evidence that previously reported risk factors of body mass index (BMI; 1.46; 1.20-1.78) and hip circumference (1.42; 1.21-1.67) were associated with pancreatic cancer. We also found evidence of novel associations with metabolites that have not previously been implicated in pancreatic cancer: *, a fibrinogen-cleavage peptide (1.60; 1.31-1.95), and O-sulfo-l-tyrosine (0.58; 0.46-0.74). An inverse association was also observed with lung adenocarcinoma (0.63; 0.54-0.74).

Conclusions: Markers of adiposity (BMI and hip circumference) are potential intervention targets for pancreatic cancer prevention. Further clarification of the causal relevance of the fibrinogen-cleavage peptides and O-sulfo-l-tyrosine in pancreatic cancer etiology is required, as is the basis of our observed association with lung adenocarcinoma.

Impact: For pancreatic cancer, MR-PheWAS can augment existing risk factor knowledge and generate novel hypotheses to investigate.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0036DOI Listing
December 2019

Commentary: Orienting causal relationships between two phenotypes using bidirectional Mendelian randomization.

Int J Epidemiol 2019 06;48(3):907-911

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.

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http://dx.doi.org/10.1093/ije/dyz149DOI Listing
June 2019

DNA methylation links prenatal smoking exposure to later life health outcomes in offspring.

Clin Epigenetics 2019 07 1;11(1):97. Epub 2019 Jul 1.

Center for Life Course Health Research, University of Oulu, Oulu, Finland.

Background: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship.

Methods: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring.

Results: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes.

Conclusions: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.
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http://dx.doi.org/10.1186/s13148-019-0683-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604191PMC
July 2019

An integrative approach to detect epigenetic mechanisms that putatively mediate the influence of lifestyle exposures on disease susceptibility.

Int J Epidemiol 2019 06;48(3):887-898

MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.

Background: There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation. It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence in this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNA methylation levels on disease susceptibility.

Methods: To illustrate our approach, we identified 412 CpG sites where DNA methylation was associated with prenatal smoking. We then applied 2SMR to investigate potential downstream effects of these putative changes on 643 complex traits using findings from large-scale genome-wide association studies. To strengthen evidence of mediatory mechanisms, we used multiple-trait colocalization to assess whether DNA methylation, nearby gene expression and complex trait variation were all influenced by the same causal genetic variant.

Results: We identified 22 associations that survived multiple testing (P < 1.89 × 10-7). In-depth follow-up analyses of particular note suggested that the associations between DNA methylation at the ASPSCR1 and REST/POL2RB gene regions, both linked with reduced lung function, may be mediated by changes in gene expression. We validated associations between DNA methylation and traits using independent samples from different stages across the life course.

Conclusion: Our approach should prove valuable in prioritizing CpG sites that may mediate the effect of causal risk factors on disease. In-depth evaluations of findings are necessary to robustly disentangle causality from alternative explanations such as horizontal pleiotropy.
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http://dx.doi.org/10.1093/ije/dyz119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659375PMC
June 2019

Investigating causal relations between sleep traits and risk of breast cancer in women: mendelian randomisation study.

BMJ 2019 Jun 26;365:l2327. Epub 2019 Jun 26.

MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.

Objective: To examine whether sleep traits have a causal effect on risk of breast cancer.

Design: Mendelian randomisation study.

Setting: UK Biobank prospective cohort study and Breast Cancer Association Consortium (BCAC) case-control genome-wide association study.

Participants: 156 848 women in the multivariable regression and one sample mendelian randomisation (MR) analysis in UK Biobank (7784 with a breast cancer diagnosis) and 122 977 breast cancer cases and 105 974 controls from BCAC in the two sample MR analysis.

Exposures: Self reported chronotype (morning or evening preference), insomnia symptoms, and sleep duration in multivariable regression, and genetic variants robustly associated with these sleep traits.

Main Outcome Measure: Breast cancer diagnosis.

Results: In multivariable regression analysis using UK Biobank data on breast cancer incidence, morning preference was inversely associated with breast cancer (hazard ratio 0.95, 95% confidence interval 0.93 to 0.98 per category increase), whereas there was little evidence for an association between sleep duration and insomnia symptoms. Using 341 single nucleotide polymorphisms (SNPs) associated with chronotype, 91 SNPs associated with sleep duration, and 57 SNPs associated with insomnia symptoms, one sample MR analysis in UK Biobank provided some supportive evidence for a protective effect of morning preference on breast cancer risk (0.85, 0.70, 1.03 per category increase) but imprecise estimates for sleep duration and insomnia symptoms. Two sample MR using data from BCAC supported findings for a protective effect of morning preference (inverse variance weighted odds ratio 0.88, 95% confidence interval 0.82 to 0.93 per category increase) and adverse effect of increased sleep duration (1.19, 1.02 to 1.39 per hour increase) on breast cancer risk (both oestrogen receptor positive and oestrogen receptor negative), whereas evidence for insomnia symptoms was inconsistent. Results were largely robust to sensitivity analyses accounting for horizontal pleiotropy.

Conclusions: Findings showed consistent evidence for a protective effect of morning preference and suggestive evidence for an adverse effect of increased sleep duration on breast cancer risk.
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http://dx.doi.org/10.1136/bmj.l2327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592406PMC
June 2019
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