المؤلفون: Monasso, Giulietta S, Hoang, Thanh T, Mancano, Giulia, Fernández-Barrés, Sílvia, Dou, John, Jaddoe, Vincent WV, Page, Christian M, Johnson, Laura, Bustamante, Mariona, Bakulski, Kelly M, Håberg, Siri E, Ueland, Per M, Battram, Thomas, Merid, Simon K, Melén, Erik, Caramaschi, Doretta, Küpers, Leanne K, Sunyer, Jordi, Nystad, Wenche, Heil, Sandra G, Schmidt, Rebecca J, Vrijheid, Martine, Sharp, Gemma C, London, Stephanie J, Felix, Janine F

المصدر: Epigenetics. 18(1)

مصطلحات موضوعية: Biological Sciences, Genetics, Pediatric, Prevention, Nutrition, Perinatal Period - Conditions Originating in Perinatal Period, Reproductive health and childbirth, Good Health and Well Being, Infant, Newborn, Pregnancy, Child, Female, Humans, DNA Methylation, Epigenome, Birth Weight, Vitamin B 12, Epigenesis, Genetic, Fetal Blood, Vitamin B12, DNA methylation, epidemiology, cohort study, meta-analysis, PACE consortium, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Developmental Biology, Biochemistry and cell biology

الوصف: Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8xv4n01bTest

المؤلفون: Battram, Thomas

المساهمون: Gaunt, Tom, Hemani, Gibran, Timpson, Nicholas

مصطلحات موضوعية: Thesis, EWAS

الوصف: Quantifying underlying DNA methylation signatures of complex traits presents an opportunity to identify biomarkers and modes of disease intervention. Years of epigenome-wide association studies (EWAS) have shown signatures vary greatly by trait and the interpretation of signals remains difficult. This thesis explores potential explanations for this and examines the role of EWAS in understanding complex traits. To ascertain necessary data, I led a collection of EWAS results and developed a web resource for storing and querying the 975,574 associations across 1244 EWAS. Evidence was found that results for EWAS that accounted for common biases, such as batch effects and cell composition, could partially be explained by variance and heritability of DNA methylation. Further, identified sites were enriched in promoter regions, enhancer regions and transcription factor binding sites. Across the EWAS surveyed, DNA methylation was commonly measured in blood at roughly 450,000 sites genome-wide. I examined the predictive capacity of DNA methylation in this context and found that it captured little variance of 400 independent complex traits. Next, commonalities between the overlap in biology highlighted by EWAS and GWAS of corresponding traits was explored and I found that the genes and genesets identified were substantially different. Trait aetiology may still be explored through EWAS, but the largely differential biology highlighted suggests the majority of EWAS results here are due to confounding and reverse causation. Mendelian randomization (MR) analyses further suggested residual confounding as being responsible for EWAS results as marked differences were found between an EWAS meta-analysis of lung cancer and the corresponding MR analyses. Through cataloguing published results and integrating methods and results from other fields, this thesis identifies limitations to the current EWAS study design that reveal the complexity of the role of DNA methylation on mediating the path from genotype or environment to phenotype.

الوصول الحر: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.831506Test

المؤلفون: Monasso, Giulietta S., Hoang, Thanh T., Mancano, Giulia, Fernández-Barrés, Sílvia, Dou, John, Jaddoe, Vincent W.V., Page, Christian M., Johnson, Laura, Bustamante, Mariona, Bakulski, Kelly M., Håberg, Siri E., Ueland, Per M., Battram, Thomas, Merid, Simon K., Melén, Erik, Caramaschi, Doretta, Küpers, Leanne K., Sunyer, Jordi, Nystad, Wenche, Heil, Sandra G., Schmidt, Rebecca J., Vrijheid, Martine, Sharp, Gemma C., London, Stephanie J., Felix, Janine F.

المصدر: Monasso , G S , Hoang , T T , Mancano , G , Fernández-Barrés , S , Dou , J , Jaddoe , V W V , Page , C M , Johnson , L , Bustamante , M , Bakulski , K M , Håberg , S E , Ueland , P M , Battram , T , Merid , S K , Melén , E , Caramaschi , D , Küpers , L K , Sunyer , J , Nystad , W , Heil , S G , Schmidt , R J , Vrijheid , M ....

مصطلحات موضوعية: /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, name=SDG 3 - Good Health and Well-being

الوصف: Circulating vitamin B12 concentrations during pregnancy are associated with offspring health. Foetal DNA methylation changes could underlie these associations. Within the Pregnancy And Childhood Epigenetics Consortium, we meta-analysed epigenome-wide associations of circulating vitamin B12 concentrations in mothers during pregnancy (n = 2,420) or cord blood (n = 1,029), with cord blood DNA methylation. Maternal and newborn vitamin B12 concentrations were associated with DNA methylation at 109 and 7 CpGs, respectively (False Discovery Rate P-value <0.05). Persistent associations with DNA methylation in the peripheral blood of up to 482 children aged 4–10 y were observed for 40.7% of CpGs associated with maternal vitamin B12 and 57.1% of CpGs associated with newborn vitamin B12. Of the CpGs identified in the maternal meta-analyses, 4.6% were associated with either birth weight or gestational age in a previous work. For the newborn meta-analysis, this was the case for 14.3% of the identified CpGs. Also, of the CpGs identified in the newborn meta-analysis, 14.3% and 28.6%, respectively, were associated with childhood cognitive skills and nonverbal IQ. Of the 109 CpGs associated with maternal vitamin B12, 18.3% were associated with nearby gene expression. In this study, we showed that maternal and newborn vitamin B12 concentrations are associated with DNA methylation at multiple CpGs in offspring blood (P FDR <0.05). Whether this differential DNA methylation underlies associations of vitamin B12 concentrations with child health outcomes, such as birth weight, gestational age, and childhood cognition, should be further examined in future studies.

وصف الملف: application/pdf

العلاقة: https://pure.eur.nl/en/publications/0fac3bc6-ced4-45b4-852e-d3db9302f406Test

الإتاحة: https://doi.org/10.1080/15592294.2023.2202835Test
https://pure.eur.nl/en/publications/0fac3bc6-ced4-45b4-852e-d3db9302f406Test
https://pure.eur.nl/ws/files/94842190/A_meta_analysis_of_epigenome_wide_association_studies_on_pregnancy_vitami.pdfTest
http://www.scopus.com/inward/record.url?scp=85153275865&partnerID=8YFLogxKTest

المؤلفون: Battram, Thomas, Richmond, Rebecca C., Baglietto, Laura, Haycock, Philip C., Perduca, Vittorio, Bojesen, Stig E., Gaunt, Tom R., Hemani, Gibran, Guida, Florence, Carreras-Torres, Robert, Hung, Rayjean, Amos, Christopher, I, Freeman, Joshua R., Sandanger, Torkjel M., Nøst, Therese H., Nordestgaard, Børge G., Teschendorff, Andrew E., Polidoro, Silvia, Vineis, Paolo, Severi, Gianluca, Hodge, Allison M., Giles, Graham G., Grankvist, Kjell, Johansson, Mikael, Johansson, Mattias, Smith, George Davey, Relton, Caroline L.

المصدر: International Journal of Epidemiology. 48(5):1493-1504

مصطلحات موضوعية: Lung cancer, DNA methylation, Mendelian randomization, ALSPAC, ARIES

الوصف: 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.

وصف الملف: electronic

الوصول الحر: https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-167007Test
https://doi.org/10.1093/ije/dyz190Test
https://umu.diva-portal.org/smash/get/diva2:1383781/FULLTEXT01.pdfTest

المؤلفون: Battram, Thomas, Yousefi, Paul, Crawford, Gemma, Prince, Claire, Babaei, Mahsa Sheikhali, Sharp, Gemma, Hatcher, Charlie, Vega-Salas, María Jesús, Khodabakhsh, Sahar, Whitehurst, Oliver, Langdon, Ryan, Mahoney, Luke, Mancano, Giulia, Lee, Matthew A., Watkins, Sarah H., Hemani, Gibran, Suderman, Matthew

المساهمون: Elliott, Hannah R., Lay, Abigail C., Gaunt, Tom R., Relton, Caroline L., Staley, James R.

المصدر: Battram , T , Yousefi , P , Crawford , G , Prince , C , Babaei , M S , Sharp , G , Hatcher , C , Vega-Salas , M J , Khodabakhsh , S , Whitehurst , O , Langdon , R , Mahoney , L , Elliott , H R (ed.) , Mancano , G , Lee , M A , Watkins , S H , Lay , A C (ed.) , Hemani , G , Gaunt , T R (ed.) , Relton , C L (ed.) , Staley , J R (ed.) & Suderman ....

الوصف: Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p

الإتاحة: https://doi.org/10.12688/wellcomeopenres.17598.1Test
https://research.manchester.ac.uk/en/publications/f6d4f834-c7d3-477f-b6dd-c41da12fa573Test

المؤلفون: Lee, Matthew, Hatcher, Charlie A, McGuinness, Luke, Mcbride, Nancy S, Battram, Thomas M, Wan, Wenxin, Fang, Si, Wade, Kaitlin H, Corbin, Laura J, Timpson, Nicholas John

المصدر: Lee , M , Hatcher , C A , McGuinness , L , Mcbride , N S , Battram , T M , Wan , W , Fang , S , Wade , K H , Corbin , L J & Timpson , N J 2022 , ' Systematic review and meta-analyses : What has the application of Mendelian randomization told us about the causal effect of adiposity on health outcomes? ' , Wellcome Open Research , vol. 7 , no. 308 . https://doi.org/10.12688/wellcomeopenres.18657.1Test

الوصف: Mendelian randomization (MR) is increasingly used for generating estimates of the causal impact of exposures on outcomes. Evidence suggests a causal role of excess adipose tissue (adiposity) on many health outcomes. However, this body of work has not been systematically appraised. We systematically reviewed and meta-analysed results from MR studies investigating the association between adiposity and health outcomes prior to the SARS-CoV-2/COVID-19 pandemic (PROSPERO: CRD42018096684). We searched Medline, EMBASE, and bioRxiv up to February 2019 and obtained data on 2,214 MR analyses from 173 included articles. 29 meta-analyses were conducted using data from 34 articles (including 66 MR analyses) and results not able to be meta-analysed were narratively synthesised. Body mass index (BMI) was the predominant exposure used and was primarily associated with an increase in investigated outcomes; the largest effect in the meta-analyses was observed for the association between BMI and polycystic ovary syndrome (estimates reflect odds ratios (OR) per standard deviation change in each adiposity measure): OR = 2.55; 95% confidence interval (CI) = 1.22–5.33. Only colorectal cancer was investigated with two exposures in the meta-analysis: BMI (OR = 1.18; 95% CI = 1.01–1.37) and waist-hip ratio (WHR; OR = 1.48; 95% CI = 1.08–2.03). Broadly, results were consistent across the meta-analyses and narrative synthesis. Consistent with many observational studies, this work highlights the impact of adiposity across a broad spectrum of health outcomes, enabling targeted follow-up analyses. However, missing and incomplete data mean results should be interpreted with caution.

وصف الملف: application/pdf

العلاقة: https://research-information.bris.ac.uk/en/publications/2ea7a686-d396-484e-88b4-a3d47e13f0edTest

الإتاحة: https://doi.org/10.12688/wellcomeopenres.18657.1Test
https://hdl.handle.net/1983/2ea7a686-d396-484e-88b4-a3d47e13f0edTest
https://research-information.bris.ac.uk/en/publications/2ea7a686-d396-484e-88b4-a3d47e13f0edTest
https://research-information.bris.ac.uk/ws/files/354508722/manuscript_WO1_MAL1_2_.pdfTest

المؤلفون: Battram, Thomas, Yousefi, Paul, Crawford, Gemma, Prince, Claire, Sheikhali Babaei, Mahsa, Sharp, Gemma, Hatcher, Charlie, Vega-Salas, María Jesús, Khodabakhsh, Sahar, Whitehurst, Oliver, Langdon, Ryan, Mahoney, Luke, Elliott, Hannah R, Mancano, Giulia, Lee, Matthew A, Watkins, Sarah H, Lay, Abigail C, Hemani, Gibran, Gaunt, Tom R, Relton, Caroline L, Staley, James R, Suderman, Matthew

المصدر: Battram , T , Yousefi , P , Crawford , G , Prince , C , Sheikhali Babaei , M , Sharp , G , Hatcher , C , Vega-Salas , M J , Khodabakhsh , S , Whitehurst , O , Langdon , R , Mahoney , L , Elliott , H R , Mancano , G , Lee , M A , Watkins , S H , Lay , A C , Hemani , G , Gaunt , T R , Relton , C L , Staley , J R & Suderman , M 2022 , ' ....

مصطلحات موضوعية: /dk/atira/pure/core/keywords/alspac, name=ALSPAC, /dk/atira/pure/core/keywords/population_health_SRI, name=Bristol Population Health Science Institute

الوصف: Epigenome-wide association studies (EWAS) seek to quantify associations between traits/exposures and DNA methylation measured at thousands or millions of CpG sites across the genome. In recent years, the increase in availability of DNA methylation measures in population-based cohorts and case-control studies has resulted in a dramatic expansion of the number of EWAS being performed and published. To make this rich source of results more accessible, we have manually curated a database of CpG-trait associations (with p<1x10 -4) from published EWAS, each assaying over 100,000 CpGs in at least 100 individuals. From January 7, 2022, The EWAS Catalog contained 1,737,746 associations from 2,686 EWAS. This includes 1,345,398 associations from 342 peer-reviewed publications. In addition, it also contains summary statistics for 392,348 associations from 427 EWAS, performed on data from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Gene Expression Omnibus (GEO). The database is accompanied by a web-based tool and R package, giving researchers the opportunity to query EWAS associations quickly and easily, and gain insight into the molecular underpinnings of disease as well as the impact of traits and exposures on the DNA methylome. The EWAS Catalog is available at http://www.ewascatalog.orgTest.

وصف الملف: application/pdf

العلاقة: https://research-information.bris.ac.uk/en/publications/afd8899f-20d6-4417-81eb-50bc42e85407Test

الإتاحة: https://doi.org/10.12688/wellcomeopenres.17598.2Test
https://hdl.handle.net/1983/afd8899f-20d6-4417-81eb-50bc42e85407Test
https://research-information.bris.ac.uk/en/publications/afd8899f-20d6-4417-81eb-50bc42e85407Test
https://research-information.bris.ac.uk/ws/files/326612483/0a595c52_1b08_490c_9acc_c16cca68c2fc_17598_thomas_battram_v2_1_.pdfTest

المؤلفون: Battram, Thomas, Gaunt, Tom R., Relton, Caroline L., Timpson, Nicholas J., Hemani, Gibran

المساهمون: Wellcome Trust, RCUK | Medical Research Council

المصدر: Nature Communications ; volume 13, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Identifying genomic regions pertinent to complex traits is a common goal of genome-wide and epigenome-wide association studies (GWAS and EWAS). GWAS identify causal genetic variants, directly or via linkage disequilibrium, and EWAS identify variation in DNA methylation associated with a trait. While GWAS in principle will only detect variants due to causal genes, EWAS can also identify genes via confounding, or reverse causation. We systematically compare GWAS ( N > 50,000) and EWAS ( N > 4500) results of 15 complex traits. We evaluate if the genes or gene ontology terms flagged by GWAS and EWAS overlap, and find substantial overlap for diastolic blood pressure, (gene overlap P = 5.2 × 10 −6 ; term overlap P = 0.001). We superimpose our empirical findings against simulated models of varying genetic and epigenetic architectures and observe that in most cases GWAS and EWAS are likely capturing distinct genesets. Our results indicate that GWAS and EWAS are capturing different aspects of the biology of complex traits.

الإتاحة: https://doi.org/10.1038/s41467-022-35037-3Test
https://www.nature.com/articles/s41467-022-35037-3.pdfTest
https://www.nature.com/articles/s41467-022-35037-3Test

المؤلفون: Sun, Yi-Qian, Richmond, Rebecca C., Suderman, Matthew, Min, Josine L, Battram, Thomas, Flatberg, Arnar, Beisvag, Vidar, Nøst, Therese Haugdahl, Guida, Florence, Jiang, Lin, Wahl, Sissel Gyrid Freim, Langhammer, Arnulf, Skorpen, Frank, Walker, Rosie M, Bretherick, Andrew D, Zeng, Yanni, Chen, Yue, Johansson, Mattias, Sandanger, Torkjel M, Relton, Caroline L, Mai, Xiao-Mei

مصطلحات موضوعية: VDP::Medical disciplines: 700, VDP::Medisinske Fag: 700

الوصف: 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.

العلاقة: International Journal of Epidemiology; Samarbeidsorganet mellom Helse Midt-Norge og NTNU: 2018/42794; Kreftforeningen: 182688-2016; Sun YQ, Richmond RC, Suderman M, Min JL, Battram T, Flatberg A, Beisvag V, Nøst TH, Guida F, Jiang L, Wahl Sgf, Langhammer A, Skorpen F, Walker, Bretherick, Zeng, Chen Y, Johansson M, Sandanger TM, Relton CL, Mai XM. Assessing the role of genome-wide DNA methylation between smoking and risk of lung cancer using repeated measurements: the HUNT Study. International Journal of Epidemiology. 2021; FRIDAID 1900392; https://hdl.handle.net/10037/21625Test

الإتاحة: https://doi.org/10.1093/ije/dyab044Test
https://hdl.handle.net/10037/21625Test

المؤلفون: Howe, Laurence J., Battram, Thomas, Morris, Tim T., Hartwig, Fernando P., Hemani, Gibran, Davies, Neil Martin, Smith, George Davey

المصدر: 1-18 ; 17 ; PLoS Genetics ; 11

الوصف: Spousal comparisons have been proposed as a design that can both reduce confounding and estimate effects of the shared adulthood environment. However, assortative mating, the process by which individuals select phenotypically (dis)similar mates, could distort associations when comparing spouses. We evaluated the use of spousal comparisons, as in the within-spouse pair (WSP) model, for aetiological research such as genetic association studies. We demonstrated that the WSP model can reduce confounding but may be susceptible to collider bias arising from conditioning on assorted spouse pairs. Analyses using UK Biobank spouse pairs found that WSP genetic association estimates were smaller than estimates from random pairs for height, educational attainment, and BMI variants. Within-sibling pair estimates, robust to demographic and parental effects, were also smaller than random pair estimates for height and educational attainment, but not for BMI. WSP models, like other within-family models, may reduce confounding from demographic factors in genetic association estimates, and so could be useful for triangulating evidence across study designs to assess the robustness of findings. However, WSP estimates should be interpreted with caution due to potential collider bias. ; publishedVersion

وصف الملف: application/pdf

العلاقة: PLoS Genetics. 2021, 17 (11), 1-18.; urn:issn:1553-7390; https://hdl.handle.net/11250/3043693Test; https://doi.org/10.1371/journal.pgen.1009883Test; cristin:1963066

الإتاحة: https://doi.org/10.1371/journal.pgen.1009883Test
https://hdl.handle.net/11250/3043693Test