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1. Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study

Author

Hoang, Thanh T, Qi, Cancan, Paul, Kimberly C, Lee, Mikyeong, White, Julie D, Richards, Marie, Auerbach, Scott S, Long, Stuart, Shrestha, Srishti, Wang, Tianyuan, Freeman, Laura E Beane, Hofmann, Jonathan N, Parks, Christine, Consortium, BIOS, Xu, Cheng-Jian, Ritz, Beate, Koppelman, Gerard H, and London, Stephanie J

Subjects
Health Sciences, Lung, Genetics, Case-Control Studies, DNA Methylation, Epigenome, Humans, Male, Pesticides, BIOS Consortium, Environmental Sciences, Medical and Health Sciences, Toxicology, Biomedical and clinical sciences, Environmental sciences, Health sciences
Abstract

BackgroundPesticide exposure is associated with many long-term health outcomes; the potential underlying mechanisms are not well established for most associations. Epigenetic modifications, such as DNA methylation, may contribute. Individual pesticides may be associated with specific DNA methylation patterns but no epigenome-wide association study (EWAS) has evaluated methylation in relation to individual pesticides.ObjectivesWe conducted an EWAS of DNA methylation in relation to several pesticide active ingredients.MethodsThe Agricultural Lung Health Study is a case-control study of asthma, nested within the Agricultural Health Study. We analyzed blood DNA methylation measured using Illumina's EPIC array in 1,170 male farmers of European ancestry. For pesticides still on the market at blood collection (2009-2013), we evaluated nine active ingredients for which at least 30 participants reported past and current (within the last 12 months) use, as well as seven banned organochlorines with at least 30 participants reporting past use. We used robust linear regression to compare methylation at individual C-phosphate-G sites (CpGs) among users of a specific pesticide to never users.ResultsUsing family-wise error rate (p

Published
2021

2. Residential PM2.5 exposure and the nasal methylome in children

Author

Sordillo, Joanne E, Cardenas, Andres, Qi, Cancan, Rifas-Shiman, Sheryl L, Coull, Brent, Luttmann-Gibson, Heike, Schwartz, Joel, Kloog, Itai, Hivert, Marie-France, DeMeo, Dawn L, Baccarelli, Andrea A, Xu, Cheng-Jian, Gehring, Ulrike, Vonk, Judith M, Koppelman, Gerard, Oken, Emily, and Gold, Diane R

Subjects
Biological Sciences, Genetics, Climate-Related Exposures and Conditions, Pediatric, Lung, Human Genome, Clinical Research, Adolescent, Air Pollution, Child, DNA Methylation, Epigenome, Humans, Netherlands, Particulate Matter, Environmental Sciences
Abstract

RationalePM2.5-induced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.ObjectivesWe aimed to study associations of fine particulate matter PM2.5 exposure with DNA methylation in nasal cells.MethodsWe conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM2.5 at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).ResultsIn adjusted analyses, we found 362 CpGs associated with 1-year PM2.5 (FDR

Published
2021

3. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Author

Vehmeijer, Florianne OL, Küpers, Leanne K, Sharp, Gemma C, Salas, Lucas A, Lent, Samantha, Jima, Dereje D, Tindula, Gwen, Reese, Sarah, Qi, Cancan, Gruzieva, Olena, Page, Christian, Rezwan, Faisal I, Melton, Philip E, Nohr, Ellen, Escaramís, Geòrgia, Rzehak, Peter, Heiskala, Anni, Gong, Tong, Tuominen, Samuli T, Gao, Lu, Ross, Jason P, Starling, Anne P, Holloway, John W, Yousefi, Paul, Aasvang, Gunn Marit, Beilin, Lawrence J, Bergström, Anna, Binder, Elisabeth, Chatzi, Leda, Corpeleijn, Eva, Czamara, Darina, Eskenazi, Brenda, Ewart, Susan, Ferre, Natalia, Grote, Veit, Gruszfeld, Dariusz, Håberg, Siri E, Hoyo, Cathrine, Huen, Karen, Karlsson, Robert, Kull, Inger, Langhendries, Jean-Paul, Lepeule, Johanna, Magnus, Maria C, Maguire, Rachel L, Molloy, Peter L, Monnereau, Claire, Mori, Trevor A, Oken, Emily, Räikkönen, Katri, Rifas-Shiman, Sheryl, Ruiz-Arenas, Carlos, Sebert, Sylvain, Ullemar, Vilhelmina, Verduci, Elvira, Vonk, Judith M, Xu, Cheng-jian, Yang, Ivana V, Zhang, Hongmei, Zhang, Weiming, Karmaus, Wilfried, Dabelea, Dana, Muhlhausler, Beverly S, Breton, Carrie V, Lahti, Jari, Almqvist, Catarina, Jarvelin, Marjo-Riitta, Koletzko, Berthold, Vrijheid, Martine, Sørensen, Thorkild IA, Huang, Rae-Chi, Arshad, Syed Hasan, Nystad, Wenche, Melén, Erik, Koppelman, Gerard H, London, Stephanie J, Holland, Nina, Bustamante, Mariona, Murphy, Susan K, Hivert, Marie-France, Baccarelli, Andrea, Relton, Caroline L, Snieder, Harold, Jaddoe, Vincent WV, and Felix, Janine F

Subjects
Biological Sciences, Genetics, Pediatric, Nutrition, Prevention, Human Genome, Obesity, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cardiovascular, Cancer, Stroke, Oral and gastrointestinal, Adolescent, Body Mass Index, Child, Child, Preschool, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Epigenome, Female, Fetal Blood, Humans, Male, Parturition, Pediatric Obesity, Pregnancy, Body mass index, Childhood obesity, DNA methylation, Epigenetics, Clinical Sciences
Abstract

BackgroundDNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.MethodsWe examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.ResultsDNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P

Published
2020

4. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Author

Merid, Simon Kebede, Novoloaca, Alexei, Sharp, Gemma C, Küpers, Leanne K, Kho, Alvin T, Roy, Ritu, Gao, Lu, Annesi-Maesano, Isabella, Jain, Pooja, Plusquin, Michelle, Kogevinas, Manolis, Allard, Catherine, Vehmeijer, Florianne O, Kazmi, Nabila, Salas, Lucas A, Rezwan, Faisal I, Zhang, Hongmei, Sebert, Sylvain, Czamara, Darina, Rifas-Shiman, Sheryl L, Melton, Phillip E, Lawlor, Debbie A, Pershagen, Göran, Breton, Carrie V, Huen, Karen, Baiz, Nour, Gagliardi, Luigi, Nawrot, Tim S, Corpeleijn, Eva, Perron, Patrice, Duijts, Liesbeth, Nohr, Ellen Aagaard, Bustamante, Mariona, Ewart, Susan L, Karmaus, Wilfried, Zhao, Shanshan, Page, Christian M, Herceg, Zdenko, Jarvelin, Marjo-Riitta, Lahti, Jari, Baccarelli, Andrea A, Anderson, Denise, Kachroo, Priyadarshini, Relton, Caroline L, Bergström, Anna, Eskenazi, Brenda, Soomro, Munawar Hussain, Vineis, Paolo, Snieder, Harold, Bouchard, Luigi, Jaddoe, Vincent W, Sørensen, Thorkild IA, Vrijheid, Martine, Arshad, S Hasan, Holloway, John W, Håberg, Siri E, Magnus, Per, Dwyer, Terence, Binder, Elisabeth B, DeMeo, Dawn L, Vonk, Judith M, Newnham, John, Tantisira, Kelan G, Kull, Inger, Wiemels, Joseph L, Heude, Barbara, Sunyer, Jordi, Nystad, Wenche, Munthe-Kaas, Monica C, Räikkönen, Katri, Oken, Emily, Huang, Rae-Chi, Weiss, Scott T, Antó, Josep Maria, Bousquet, Jean, Kumar, Ashish, Söderhäll, Cilla, Almqvist, Catarina, Cardenas, Andres, Gruzieva, Olena, Xu, Cheng-Jian, Reese, Sarah E, Kere, Juha, Brodin, Petter, Solomon, Olivia, Wielscher, Matthias, Holland, Nina, Ghantous, Akram, Hivert, Marie-France, Felix, Janine F, Koppelman, Gerard H, London, Stephanie J, and Melén, Erik

Subjects
Humans, Premature Birth, DNA, DNA Methylation, Fetal Development, Adolescent, Child, Child, Preschool, Infant, Newborn, Infant, Premature, Female, Male, Genetic Loci, Epigenome, Development, Epigenetics, Gestational age, Preterm birth, Transcriptomics, Preschool, Infant, Newborn, Premature, Genetics, Clinical Sciences
Abstract

BackgroundPreterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.MethodsWe performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.ResultsWe identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P

Published
2020

5. Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Author

Küpers, Leanne K, Monnereau, Claire, Sharp, Gemma C, Yousefi, Paul, Salas, Lucas A, Ghantous, Akram, Page, Christian M, Reese, Sarah E, Wilcox, Allen J, Czamara, Darina, Starling, Anne P, Novoloaca, Alexei, Lent, Samantha, Roy, Ritu, Hoyo, Cathrine, Breton, Carrie V, Allard, Catherine, Just, Allan C, Bakulski, Kelly M, Holloway, John W, Everson, Todd M, Xu, Cheng-Jian, Huang, Rae-Chi, van der Plaat, Diana A, Wielscher, Matthias, Merid, Simon Kebede, Ullemar, Vilhelmina, Rezwan, Faisal I, Lahti, Jari, van Dongen, Jenny, Langie, Sabine AS, Richardson, Tom G, Magnus, Maria C, Nohr, Ellen A, Xu, Zongli, Duijts, Liesbeth, Zhao, Shanshan, Zhang, Weiming, Plusquin, Michelle, DeMeo, Dawn L, Solomon, Olivia, Heimovaara, Joosje H, Jima, Dereje D, Gao, Lu, Bustamante, Mariona, Perron, Patrice, Wright, Robert O, Hertz-Picciotto, Irva, Zhang, Hongmei, Karagas, Margaret R, Gehring, Ulrike, Marsit, Carmen J, Beilin, Lawrence J, Vonk, Judith M, Jarvelin, Marjo-Riitta, Bergström, Anna, Örtqvist, Anne K, Ewart, Susan, Villa, Pia M, Moore, Sophie E, Willemsen, Gonneke, Standaert, Arnout RL, Håberg, Siri E, Sørensen, Thorkild IA, Taylor, Jack A, Räikkönen, Katri, Yang, Ivana V, Kechris, Katerina, Nawrot, Tim S, Silver, Matt J, Gong, Yun Yun, Richiardi, Lorenzo, Kogevinas, Manolis, Litonjua, Augusto A, Eskenazi, Brenda, Huen, Karen, Mbarek, Hamdi, Maguire, Rachel L, Dwyer, Terence, Vrijheid, Martine, Bouchard, Luigi, Baccarelli, Andrea A, Croen, Lisa A, Karmaus, Wilfried, Anderson, Denise, de Vries, Maaike, Sebert, Sylvain, Kere, Juha, Karlsson, Robert, Arshad, Syed Hasan, Hämäläinen, Esa, Routledge, Michael N, Boomsma, Dorret I, Feinberg, Andrew P, Newschaffer, Craig J, Govarts, Eva, Moisse, Matthieu, Fallin, M Daniele, Melén, Erik, and Prentice, Andrew M

Subjects
Fetus, Humans, Prenatal Exposure Delayed Effects, Birth Weight, Folic Acid, DNA, Body Mass Index, Smoking, DNA Methylation, Epigenesis, Genetic, CpG Islands, Fetal Development, Pregnancy, Genome, Human, Adolescent, Adult, Child, Infant, Newborn, Female, Male, Genome-Wide Association Study, Epigenesis, Genetic, Genome, Human, Infant, Newborn
Abstract

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni

Published
2019

6. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

Author

Sharp, Gemma C, Salas, Lucas A, Monnereau, Claire, Allard, Catherine, Yousefi, Paul, Everson, Todd M, Bohlin, Jon, Xu, Zongli, Huang, Rae-Chi, Reese, Sarah E, Xu, Cheng-Jian, Baïz, Nour, Hoyo, Cathrine, Agha, Golareh, Roy, Ritu, Holloway, John W, Ghantous, Akram, Merid, Simon K, Bakulski, Kelly M, Küpers, Leanne K, Zhang, Hongmei, Richmond, Rebecca C, Page, Christian M, Duijts, Liesbeth, Lie, Rolv T, Melton, Phillip E, Vonk, Judith M, Nohr, Ellen A, Williams-DeVane, ClarLynda, Huen, Karen, Rifas-Shiman, Sheryl L, Ruiz-Arenas, Carlos, Gonseth, Semira, Rezwan, Faisal I, Herceg, Zdenko, Ekström, Sandra, Croen, Lisa, Falahi, Fahimeh, Perron, Patrice, Karagas, Margaret R, Quraishi, Bilal M, Suderman, Matthew, Magnus, Maria C, Jaddoe, Vincent WV, Taylor, Jack A, Anderson, Denise, Zhao, Shanshan, Smit, Henriette A, Josey, Michele J, Bradman, Asa, Baccarelli, Andrea A, Bustamante, Mariona, Håberg, Siri E, Pershagen, Göran, Hertz-Picciotto, Irva, Newschaffer, Craig, Corpeleijn, Eva, Bouchard, Luigi, Lawlor, Debbie A, Maguire, Rachel L, Barcellos, Lisa F, Smith, George Davey, Eskenazi, Brenda, Karmaus, Wilfried, Marsit, Carmen J, Hivert, Marie-France, Snieder, Harold, Fallin, M Daniele, Melén, Erik, Munthe-Kaas, Monica C, Arshad, Hasan, Wiemels, Joseph L, Annesi-Maesano, Isabella, Vrijheid, Martine, Oken, Emily, Holland, Nina, Murphy, Susan K, Sørensen, Thorkild IA, Koppelman, Gerard H, Newnham, John P, Wilcox, Allen J, Nystad, Wenche, London, Stephanie J, Felix, Janine F, and Relton, Caroline L

Subjects
Biological Sciences, Genetics, Perinatal Period - Conditions Originating in Perinatal Period, Contraception/Reproduction, Pediatric, Human Genome, Obesity, 2.1 Biological and endogenous factors, Aetiology, Reproductive health and childbirth, Adult, Body Mass Index, Cohort Studies, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Humans, Infant, Newborn, Male, Maternal Inheritance, Mothers, Pregnancy, Pregnancy Outcome, Prenatal Exposure Delayed Effects, Medical and Health Sciences, Genetics & Heredity
Abstract

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (

Published
2017

7. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

Author

Joubert, Bonnie R, Felix, Janine F, Yousefi, Paul, Bakulski, Kelly M, Just, Allan C, Breton, Carrie, Reese, Sarah E, Markunas, Christina A, Richmond, Rebecca C, Xu, Cheng-Jian, Küpers, Leanne K, Oh, Sam S, Hoyo, Cathrine, Gruzieva, Olena, Söderhäll, Cilla, Salas, Lucas A, Baïz, Nour, Zhang, Hongmei, Lepeule, Johanna, Ruiz, Carlos, Ligthart, Symen, Wang, Tianyuan, Taylor, Jack A, Duijts, Liesbeth, Sharp, Gemma C, Jankipersadsing, Soesma A, Nilsen, Roy M, Vaez, Ahmad, Fallin, M Daniele, Hu, Donglei, Litonjua, Augusto A, Fuemmeler, Bernard F, Huen, Karen, Kere, Juha, Kull, Inger, Munthe-Kaas, Monica Cheng, Gehring, Ulrike, Bustamante, Mariona, Saurel-Coubizolles, Marie José, Quraishi, Bilal M, Ren, Jie, Tost, Jörg, Gonzalez, Juan R, Peters, Marjolein J, Håberg, Siri E, Xu, Zongli, van Meurs, Joyce B, Gaunt, Tom R, Kerkhof, Marjan, Corpeleijn, Eva, Feinberg, Andrew P, Eng, Celeste, Baccarelli, Andrea A, Neelon, Sara E Benjamin, Bradman, Asa, Merid, Simon Kebede, Bergström, Anna, Herceg, Zdenko, Hernandez-Vargas, Hector, Brunekreef, Bert, Pinart, Mariona, Heude, Barbara, Ewart, Susan, Yao, Jin, Lemonnier, Nathanaël, Franco, Oscar H, Wu, Michael C, Hofman, Albert, McArdle, Wendy, Van der Vlies, Pieter, Falahi, Fahimeh, Gillman, Matthew W, Barcellos, Lisa F, Kumar, Ashish, Wickman, Magnus, Guerra, Stefano, Charles, Marie-Aline, Holloway, John, Auffray, Charles, Tiemeier, Henning W, Smith, George Davey, Postma, Dirkje, Hivert, Marie-France, Eskenazi, Brenda, Vrijheid, Martine, Arshad, Hasan, Antó, Josep M, Dehghan, Abbas, Karmaus, Wilfried, Annesi-Maesano, Isabella, Sunyer, Jordi, Ghantous, Akram, Pershagen, Göran, Holland, Nina, Murphy, Susan K, DeMeo, Dawn L, Burchard, Esteban G, Ladd-Acosta, Christine, Snieder, Harold, and Nystad, Wenche

Subjects
Genetics, Pediatric, Human Genome, Tobacco, Tobacco Smoke and Health, Prevention, Aetiology, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Respiratory, Reproductive health and childbirth, Good Health and Well Being, Asthma, Child, Child, Preschool, Chromosome Mapping, Cleft Lip, Cleft Palate, DNA Methylation, Epigenesis, Genetic, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Pregnancy, Smoking, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

Published
2016

8. Nasal DNA methylation at three CpG sites predicts childhood allergic disease

Author

van Breugel, Merlijn, Qi, Cancan, Xu, Zhongli, Pedersen, Casper-Emil T, Petoukhov, Ilya, Vonk, Judith M, Gehring, Ulrike, Berg, Marijn, Bügel, Marnix, Carpaij, Orestes A, Forno, Erick, Morin, Andréanne, Eliasen, Anders U, Jiang, Yale, van den Berge, Maarten, Nawijn, Martijn C, Li, Yang, Chen, Wei, Bont, Louis J, Bønnelykke, Klaus, Celedón, Juan C, Koppelman, Gerard H, Xu, Cheng-Jian, IRAS OH Epidemiology Chemical Agents, IRAS OH Epidemiology Chemical Agents, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Multidisciplinary, Hypersensitivity/diagnosis, General Physics and Astronomy, General Chemistry, DNA Methylation, Nose, Immunoglobulin E, Asthma/diagnosis, Asthma, General Biochemistry, Genetics and Molecular Biology, Hypersensitivity, Humans, Child, DNA Methylation/genetics
Abstract

Childhood allergic diseases, including asthma, rhinitis and eczema, are prevalent conditions that share strong genetic and environmental components. Diagnosis relies on clinical history and measurements of allergen-specific IgE. We hypothesize that a multi-omics model could accurately diagnose childhood allergic disease. We show that nasal DNA methylation has the strongest predictive power to diagnose childhood allergy, surpassing blood DNA methylation, genetic risk scores, and environmental factors. DNA methylation at only three nasal CpG sites classifies allergic disease in Dutch children aged 16 years well, with an area under the curve (AUC) of 0.86. This is replicated in Puerto Rican children aged 9–20 years (AUC 0.82). DNA methylation at these CpGs additionally detects allergic multimorbidity and symptomatic IgE sensitization. Using nasal single-cell RNA-sequencing data, these three CpGs associate with influx of T cells and macrophages that contribute to allergic inflammation. Our study suggests the potential of methylation-based allergy diagnosis.

Published
2022
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9. A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes

Author

Chu, Xiaojing, Janssen, Anna W. M., Koenen, Hans, Chang, Linzhung, He, Xuehui, Joosten, Irma, Stienstra, Rinke, Kuijpers, Yunus, Wijmenga, Cisca, Xu, Cheng-Jian, Netea, Mihai G., Tack, Cees J., Li, Yang, Buettner, Christoph, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
EXPRESSION, China, Quantitative Trait Loci, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], LOCI, Immune function, VARIANTS, General Biochemistry, Genetics and Molecular Biology, Voeding, Metabolisme en Genomica, Voeding, Humans, Genetic Predisposition to Disease, METAANALYSIS, Nutrition, General Immunology and Microbiology, General Neuroscience, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Functional genomics, General Medicine, Genomics, ASSOCIATION, Metabolism and Genomics, Diabetes Mellitus, Type 1, Phenotype, Type 1 diabetes, Metabolisme en Genomica, CELLS, RISK-FACTORS, Nutrition, Metabolism and Genomics, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Genome-Wide Association Study, Human
Abstract

The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown.Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on200 immune-cell traits and100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls.Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation.This study provides new insights into the genetic factors that affect immunological responses in T1D.This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).Every year around the world, over 100,000 people are diagnosed with type 1 diabetes. This disease develops when the immune system mistakenly destroys the cells that produce a hormone called insulin, leaving affected individuals unable to regulate their blood sugar levels. Type 1 diabetes patients must rely on regular injections of manufactured insulin to survive. The composition and activity of the human immune system is under genetic control, and people with certain changes in their genes are more susceptible than others to develop type 1 diabetes. Previous studies have identified around 60 locations in the human DNA (known as loci) associated with the condition, but it remains unclear how these loci influence the immune system and whether diabetes will emerge. Chu, Janssen, Koenen et al. explored how variations in genetic information can influence the composition of the immune system, and the type of molecules it releases to perform its role. To do so, blood samples from 243 individuals of Dutch descent with type 1 diabetes were collected, and genetic associations were investigated. The results revealed that a major type of immune actors known as T cells are under the control of genetic factors associated with type 1 diabetes susceptibility. For instance, a specific type of T cells showed shared genetic control with type 1 diabetes. In addition, 15 loci were identified that influenced immune responses in the patients. Among those, 12 have never been reported to be involved in immune responses in healthy people, implying that these regions might only regulate the immune system of individuals with type 1 diabetes and other similar disorders. Finally, Chu, Janssen, Koenen et al. propose 11 genes within the identified loci as potential targets for new diabetes medication. These results represent an important resource for researchers exploring the genetic and immune basis of type 1 diabetes, and they could open new avenues for drug development.

Published
2022

10. Shared DNA methylation signatures in childhood allergy: The MeDALL study

Author

Xu, Cheng-Jian, Gruzieva, Olena, Qi, CanCan, Esplugues, Ana, Gehring, Ulrike, Bergström, Anna, Mason, Dan, Chatzi, Leda, Porta, Daniela, Lodrup Carlsen, Karin, Baïz, Nour, Madore, Anne-Marie, Alenius, Harri, van Rijkom, Bianca, Jankipersadsing, Soesma, Van Der Vlies, Pieter, Kull, Inger, Van Hage, Marianne, Bustamante, Mariona, Lertxundi, Aitana, Torrent, Matias, Santorelli, Gillian, Fantini, Maria Pia, Hovland, Vegard, Pesce, Giancarlo, Fyhrquist, Nanna, Laatikainen, Tiina, Nawijn, Martijn, Li, Yang, Wijmenga, Cisca, Netea, Mihai, Bousquet, Jean, Anto, Josep, Laprise, Catherine, Haahtela, Tari, Annesi-Maesano, Isabella, Carlsen, Kai-Håkon, Gori, Davide, Kogevinas, Manolis, Wright, John, Söderhäll, Cilla, Vonk, Judith, Sunyer, Jordi, Melén, Erik, Koppelman, Gerard, Fantini, Maria, Epidemiology of Allergic and Respiratory Diseases Department [Paris] (EPAR), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Xu C.-J., Gruzieva O., Qi C., Esplugues A., Gehring U., Bergstrom A., Mason D., Chatzi L., Porta D., Lodrup Carlsen K.C., Baiz N., Madore A.-M., Alenius H., van Rijkom B., Jankipersadsing S.A., van der Vlies P., Kull I., van Hage M., Bustamante M., Lertxundi A., Torrent M., Santorelli G., Fantini M.P., Hovland V., Pesce G., Fyhrquist N., Laatikainen T., Nawijn M.C., Li Y., Wijmenga C., Netea M.G., Bousquet J., Anto J.M., Laprise C., Haahtela T., Annesi-Maesano I., Carlsen K.-H., Gori D., Kogevinas M., Wright J., Soderhall C., Vonk J.M., Sunyer J., Melen E., Koppelman G.H., Research Programs Unit, Biosciences, HUMI - Human Microbiome Research, HUS Inflammation Center, Department of Dermatology, Allergology and Venereology, Helsinki University Hospital Area, University of Helsinki, Groningen Research Institute for Asthma and COPD (GRIAC), and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
0301 basic medicine, Male, Allergy, MESH: Asthma, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Eczema, Immunoglobulin E, Epigenesis, Genetic, Cohort Studies, 0302 clinical medicine, MESH: DNA Methylation, MESH: Child, Immunology and Allergy, Medicine, MESH: Epigenesis, Genetic, Child, MESH: CpG Islands, MESH: Cohort Studies, DNA methylation, biology, MESH: Immunoglobulin E, Epigenetic, Methylation, 3. Good health, CpG site, 030220 oncology & carcinogenesis, Child, Preschool, MESH: Rhinitis, Allergic, Female, Epigenetics, IgE, Adolescent, MESH: Hypersensitivity, Immunology, education, Single-nucleotide polymorphism, Article, 03 medical and health sciences, MESH: Cross-Sectional Studies, children, Hypersensitivity, Humans, Asthma, MESH: Adolescent, MESH: Humans, business.industry, MESH: Transcriptome, MESH: Child, Preschool, medicine.disease, allergy, Rhinitis, Allergic, MESH: Male, 030104 developmental biology, Cross-Sectional Studies, MESH: Eczema, 3121 General medicine, internal medicine and other clinical medicine, biology.protein, CpG Islands, business, Transcriptome, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 232514.pdf (Publisher’s version ) (Open Access) BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Published
2021
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11. Nasal DNA methylation profiling of asthma and rhinitis

Author

Qi, Cancan, Jiang, Yale, Yang, Ivana V, Forno, Erick, Wang, Ting, Vonk, Judith M, Gehring, Ulrike, Smit, Henriëtte A, Milanzi, Edith B, Carpaij, Orestes A, Berg, Marijn, Hesse, Laura, Brouwer, Sharon, Cardwell, Jonathan, Vermeulen, Cornelis J, Acosta-Pérez, Edna, Canino, Glorisa, Boutaoui, Nadia, van den Berge, Maarten, Teichmann, Sarah A, Nawijn, Martijn C, Chen, Wei, Celedón, Juan C, Xu, Cheng-Jian, Koppelman, Gerard H, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, One Health Chemisch, Groningen Research Institute for Asthma and COPD (GRIAC), IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, and One Health Chemisch

Subjects
0301 basic medicine, Epigenomics, Male, Allergy, united airways, environmental exposure, CHILDREN, Immunoglobulin E, Epigenesis, Genetic, Cohort Studies, Epigenome, 0302 clinical medicine, Immunology and Allergy, Medicine, Child, Rhinitis, RISK, biology, EPITHELIAL-CELLS, Environmental exposure, Methylation, CpG site, DNA methylation, Female, Adolescent, BIRTH, Immunology, ECZEMA, Respiratory Mucosa, Article, 03 medical and health sciences, rhinitis, Humans, IGE, EXPOSURE, METAANALYSIS, Asthma, EPIGENOME-WIDE ASSOCIATION, epigenetics, business.industry, EOSINOPHILS, Epithelial Cells, DNA Methylation, medicine.disease, Black or African American, Nasal Mucosa, 030104 developmental biology, Differentially methylated regions, 030228 respiratory system, biology.protein, CpG Islands, business, Genome-Wide Association Study
Abstract

BACKGROUND: Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. OBJECTIVE: We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. METHODS: Nasal epithelial brushes were obtained from 455 children at the 16 year follow-up of the Dutch PIAMA birth cohort study. Epigenome-wide association studies (EWAS) were performed on asthma, rhinitis and asthma and/or rhinitis (AsRh) using logistic regression, and top results were replicated in two independent cohorts of African American and Puerto Rican children. Significant CpG sites (CpGs) were related to environmental exposures (pets, active and passive smoking and molds) during secondary school, and correlated to gene expression by RNA-sequencing (n=244). RESULTS: The EWAS identified CpGs significantly associated with rhinitis (n=81) and AsRh (n=75), but not with asthma. We significantly replicated 62 /81 CpGs with rhinitis, and 60/75 with AsRh, as well as one CpG with asthma. Methylation of cg03565274 was negatively associated with AsRh, and positively associated with pets exposure during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways, and expressed in immune and epithelial cells. Nasal CpGs performed well in predicting AsRh. CONCLUSIONS: We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Pets exposure may affect nasal epithelial methylation in relation to asthma and rhinitis. CLINICAL IMPLICATIONS: Nasal DNA methylation profiles may serve as biomarker of asthma and rhinitis, and can be used across different populations to predict the presence of asthma and/or rhinitis in children.

Published
2019

12. The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

Author

Middeldorp, Christel M., Mahajan, Anubha, Horikoshi, Momoko, Robertson, Neil R., Beaumont, Robin N., Bradfield, Jonathan P., Bustamante, Mariona, Cousminer, Diana L., Day, Felix R., De Silva, N. Maneka, Guxens, Monica, Mook-Kanamori, Dennis O., St Pourcain, Beate, Warrington, Nicole M., Adair, Linda S., Ahlqvist, Emma, Ahluwalia, Tarunveer S., Almgren, Peter, Ang, Wei, Atalay, Mustafa, Auvinen, Juha, Bartels, Meike, Beckmann, Jacques S., Bilbao, Jose Ramon, Bond, Tom, Borja, Judith B., Cavadino, Alana, Charoen, Pimphen, Chen, Zhanghua, Coin, Lachlan, Cooper, Cyrus, Curtin, John A., Custovic, Adnan, Das, Shikta, Davies, Gareth E., Dedoussis, George V., Duijts, Liesbeth, Eastwood, Peter R., Eliasen, Anders U., Elliott, Paul, Eriksson, Johan G., Estivill, Xavier, Fadista, Joao, Fedko, Iryna O., Frayling, Timothy M., Gaillard, Romy, Gauderman, W. James, Geller, Frank, Gilliland, Frank, Gilsanz, Vincente, Granell, Raquel, Grarup, Niels, Groop, Leif, Hadley, Dexter, Hakonarson, Hakon, Hansen, Torben, Hartman, Catharina A., Hattersley, Andrew T., Hayes, M. Geoffrey, Hebebrand, Johannes, Heinrich, Joachim, Helgeland, Oyvind, Henders, Anjali K., Henderson, John, Henriksen, Tine B., Hirschhorn, Joel N., Hivert, Marie-France, Hocher, Berthold, Holloway, John W., Holt, Patrick, Hottenga, Jouke-Jan, Hypponen, Elina, Iniguez, Carmen, Johansson, Stefan, Jugessur, Astanand, Kahonen, Mika, Kalkwarf, Heidi J., Kaprio, Jaakko, Karhunen, Ville, Kemp, John P., Kerkhof, Marjan, Koppelman, Gerard H., Korner, Antje, Kotecha, Sailesh, Kreiner-Moller, Eskil, Kulohoma, Benard, Kumar, Ashish, Kutalik, Zoltan, Lahti, Jari, Lappe, Joan M., Larsson, Henrik, Lehtimaki, Terho, Lewin, Alexandra M., Li, Jin, Lichtenstein, Paul, Lindgren, Cecilia M., Lindi, Virpi, Linneberg, Allan, Liu, Xueping, Liu, Jun, Lowe, William L., Jr., Lundstrom, Sebastian, Lyytikainen, Leo-Pekka, Ma, Ronald C. W., Mace, Aurelien, Magi, Reedik, Magnus, Per, Mamun, Abdullah A., Mannikko, Minna, Martin, Nicholas G., Mbarek, Hamdi, McCarthy, Nina S., Medland, Sarah E., Melbye, Mads, Melen, Erik, Mohlke, Karen L., Monnereau, Claire, Morgen, Camilla S., Morris, Andrew P., Murray, Jeffrey C., Myhre, Ronny, Najman, Jackob M., Nivard, Michel G., Nohr, Ellen A., Nolte, Ilja M., Ntalla, Ioanna, O'Reilly, Paul, Oberfield, Sharon E., Oken, Emily, Oldehinkel, Albertine J., Pahkala, Katja, Palviainen, Teemu, Panoutsopoulou, Kalliope, Pedersen, Oluf, Pennell, Craig E., Pershagen, Goran, Pitkanen, Niina, Plomin, Robert, Power, Christine, Prasad, Rashmi B., Prokopenko, Inga, Pulkkinen, Lea, Raikkonen, Katri, Raitakari, Olli T., Reynolds, Rebecca M., Richmond, Rebecca C., Rivadeneira, Fernando, Rodriguez, Alina, Rose, Richard J., Salem, Rany, Santa-Marina, Loreto, Saw, Seang-Mei, Schnurr, Theresia M., Scott, James G., Selzam, Saskia, Shepherd, John A., Simpson, Angela, Skotte, Line, Sleiman, Patrick M. A., Snieder, Harold, Sørensen, Thorkild I. A., Standl, Marie, Steegers, Eric A. P., Strachan, David P., Straker, Leon, Strandberg, Timo, Taylor, Michelle, Teo, Yik-Ying, Thiering, Elisabeth, Torrent, Maties, Tyrrell, Jessica, Uitterlinden, Andre G., van Beijsterveldt, Toos, van der Most, Peter J., van Duijn, Cornelia M., Viikari, Jorma, Vilor-Tejedor, Natalia, Vogelezang, Suzanne, Vonk, Judith M., Vrijkotte, Tanja G. M., Vuoksimaa, Eero, Wang, Carol A., Watkins, William J., Wichmann, H-Erich, Willemsen, Gonneke, Williams, Gail M., Wilson, James F., Wray, Naomi R., Xu, Shujing, Xu, Cheng-Jian, Yaghootkar, Hanieh, Yi, Lu, Zafarmand, Mohammad Hadi, Zeggini, Eleftheria, Zemel, Babette S., Hinney, Anke, Lakka, Timo A., Whitehouse, Andrew J. O., Sunyer, Jordi, Widen, Elisabeth E., Feenstra, Bjarke, Sebert, Sylvain, Jacobsson, Bo, Njolstad, Pal R., Stoltenberg, Camilla, Smith, George Davey, Lawlor, Debbie A., Paternoster, Lavinia, Timpson, Nicholas J., Ong, Ken K., Bisgaard, Hans, Bonnelykke, Klaus, Jaddoe, Vincent W. V., Tiemeier, Henning, Jarvelin, Marjo-Riitta, Evans, David M., Perry, John R. B., Grant, Struan F. A., Boomsma, Dorret I., Freathy, Rachel M., McCarthy, Mark I., Felix, Janine F., Sorensen, Thorkild I. A., Tiemeier, Hen-Ning, Biological Psychology, APH - Mental Health, APH - Personalized Medicine, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Methodology, APH - Health Behaviors & Chronic Diseases, Pediatrics, Epidemiology, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Groningen Research Institute for Asthma and COPD (GRIAC), Life Course Epidemiology (LCE), Public and occupational health, APH - Aging & Later Life, ARD - Amsterdam Reproduction and Development, ACS - Atherosclerosis & ischemic syndromes, APH - Global Health, Epidemiology and Data Science, Medical Research Council (MRC), Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, Department of Public Health, Clinicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Collegium for Advanced Studies, Faculty of Medicine, Timo Strandberg / Principal Investigator, Department of Medicine, Elisabeth Ingrid Maria Widen / Principal Investigator, HUS Internal Medicine and Rehabilitation, HUS Abdominal Center, Developmental Psychology Research Group, Genetic Epidemiology, Genomic Discoveries and Clinical Translation, Cognitive and Brain Aging, Middeldorp, Christel M [0000-0002-6218-0428], and Apollo - University of Cambridge Repository

Subjects
Male, Netherlands Twin Register (NTR), embarazo, Epidemiology, C840 Clinical Psychology, LD SCORE REGRESSION, humanos, LOCI, Medizin, adolescente, Genome-wide association study, BLOOD-PRESSURE, Disease, 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Pregnancy, Medicine, 030212 general & internal medicine, Early childhood, C820 Developmental Psychology, estudios de cohortes, Child, C440 Molecular Genetics, Public, Environmental & Occupational Health, Genetics, education.field_of_study, United Kingdom/epidemiology, COMMON VARIANTS, Hälsovetenskaper, adulto, A900 Others in Medicine and Dentistry, 3142 Public health care science, environmental and occupational health, 3. Good health, predicción, ddc, Childhood traits and disorders, Phenotype, Disease/genetics, Research Design, Child, Preschool, fenotipo, Female, ICEP, medicine.symptom, CHILDHOOD OBESITY, Life Sciences & Biomedicine, EArly Genetics Lifecourse Epidemiology (EAGLE) consortium, Adult, medicine.medical_specialty, Adolescent, Birth weight, Population, Consortium, Childhood Traits And Disorders, Longitudinal, enfermedad, Childhood obesity, 1117 Public Health and Health Services, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Health Sciences, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, LONGITUDINAL TWIN, METAANALYSIS, lactante, Science & Technology, Early Growth Genetics (EGG) consortium, business.industry, Infant, Newborn, Infant, predisposición genética a la enfermedad, medicine.disease, BODY-MASS, C800 Psychology, BIRTH-WEIGHT, C420 Human Genetics, United Kingdom, Low birth weight, business, diseño de la investigación, Forecasting
Abstract

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites., We are grateful to all families and participants who took part in these studies. We also acknowledge and appreciate the unique efforts of the research teams and practitioners contributing to the collection of this wealth of data. C. M. M. is supported by funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 721567. J. F. F. has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). R. M. F. and R. N. B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). D. L. C. is funded by the American Diabetes Association Grant 1-17-PDF-077. D. O. M-K. was supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). N. M. W. is supported by an Australian National Health and Medical Research Council Early Career Fellowship (APP1104818). T. S. A. was partially funded by the Gene-Diet Interactions in Obesity (GENDINOB) project on behalf of GOYA male cohort data management and analyses and acknowledges the same. S. D. was supported by National Institute of Health Research. T. M. F. is supported by the European Research Council grant: 323195 SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk).H.H.is funded by The Children's Hospital of Philadelphia Endowed Chair in Genomic Research. A. T. H. is supported by the Wellcome Trust Senior Investigator Awards (WT098395), National Institute for Health Research (NIHR) Senior Investigator Award (NF-SI-0611-10219). J. Hebebrand received grants from German Research Society, German Ministry of Education and Research. M-F. H. is currently supported by an American Diabetes Association (ADA) Pathway Program Accelerator Early Investigator Award (1-15-ACE-26). S. J. is supported by Helse Vest no. 23929, Bergen Forskningsstiftelse and KG Jebsen Foundation and University of Bergen. J. K. has been supported by the Academy of Finland Research Professor program (grants 265240 & 263278). J. P. K. is funded by a University of Queensland Development Fellowship (UQFEL1718945). H. L. has served as a speaker for Eli-Lilly and Shire and has received research grants from Shire; all outside the submitted work. C. M. L is supported by the Li Ka Shing Foundation, WT-SSI/John Fell funds and by the NIHR Biomedical Research Centre, Oxford, by Widenlife and NIH (5P50HD028138-27). S. E. M. was funded by an NHMRC Senior Reseach Fellowship (APP1103623). K. Panoutsopoulou is funded by a career development fellowship (grant 20308) and by the Wellcome Trust (WT098051). C. P. at UCL Institute of Child Health, with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. I. P. was funded in part by the Wellcome Trust (WT205915), and the European Union's Horizon 2020 research, the European Union FP7-IDEAS-ERC Advanced Grant (GEPIDIAB, ERC-AG -ERC-294785), and innovation programme (DYNAhealth, H2020-PHC-2014-633595). R. C. R. is supported by CRUK (grant number C18281/A19169). J. G. S. is supported by an NHMRC Practitioner Fellowship Grant (APP1105807). J. T.; r is funded by the European Regional Development Fund (ERDF), the European Social Fund (ESF), Convergence Programme for Cornwall and the Isles of Scilly and the Diabetes Research and Wellness Foundation Non-Clinical Fellowship. N. V-T. is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) (2015 FI_B 00636), Generalitat de Catalunya. T. G. M. V was supported by ZonMW (TOP 40-00812-98-11010. J. F. W. is supported by the MRC Human Genetics Unit quinquennial programme QTL in Health and Disease. H. Y. is funded by Diabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NL (CP2013-50). E. Z. is supported by the Wellcome Trust (098051). B. F. is supported by Novo Nordisk Foundation (12955) and an Oak Foundation Fellowship. S. S. and M-R. J. have received funding from the European Union's Horizon 2020 research and innovation programme [under grant agreement No 633595] for the DynaHEALTH action. P. R. N. was supported by the European Research Council (ERC), University of Bergen, KG Jebsen and Helse Vest. G. D. S. works within the MRC Integrative Epidemiology Unit at the University of Bristol (MC_UU_12013/1). D. A. L was supported by the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement (Grant number 669545; DevelopObese), US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MC_UU_00011/6), Wellcome Trust GWAS grant (WT088806), an NIHR Senior Investigator Award (NF-SI-0611-10196) and the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L. Paternoster was supported by the UK Medical Research Council Unit grants MC_UU_12013_5. N. J. T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 102215/2/13/2), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). V.W.V.J. received an additional grant from the Netherlands Organization for Health Research and Development (NWO, ZonMw-VIDI 016.136.361), a European Research Council Consolidator Grant (ERC-2014-CoG-648916) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 633595 (DynaHEALTH) and 733206 (LifeCycle). D. M. E. is funded by the UK Medical Research Council Unit grant MC_UU_12013_4, Australian Research Council Future Fellowship (FT130101709) and a NHMRC Senior Research Fellowship (GNT1137714). S. F. A. G. is funded by the Daniel B. Burke Endowed Chair for Diabetes Research and R01 HD056465. D. I. B. is supported by Spinozapremie (NWO-56-464-14192) and the Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB. M. I. M. is a Wellcome Senior Investgator and NIHR Senior Investigator supported by the Wellcome (090532, 098381, 203141), NIHR (NF-SI-0617-10090) and the US National Institute of Health (grant: R01 DK10324), the UK Medical Research Council (grant: MCiabetes UK RD Lawrence fellowship (grant: 17/0005594). M. H. Z was supported by BBMRI-NLNIHR Biomedical Research Centre, Oxford. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Published
2019
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13. Soluble immune markers in the different phases of chronic hepatitis B virus infection

Author

Wiegand, S., Wiegand, Steffen B., Beggel, Bastian, Wranke, Anika, Aliabadi, Elmira, Jaroszewicz, Jerzy, Xu, Cheng Jian, Li, Yang, Manns, Michael P., Lengauer, Thomas, Wedemeyer, Heiner, Kraft, Anke R.M., Falk, Christine S., Cornberg, Markus, and HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.

Subjects
Male, 0301 basic medicine, Medizin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], 0302 clinical medicine, Hepatitis B e Antigens, Young adult, Child, Multidisciplinary, virus diseases, Middle Aged, Viral Load, Hepatitis B, Prognosis, Seroconversion, Child, Preschool, Cohort, Medicine, Female, 030211 gastroenterology & hepatology, Chemokines, Adult, Hepatitis B virus, Adolescent, Science, Antiviral Agents, Article, Virus, Young Adult, 03 medical and health sciences, Hepatitis B, Chronic, medicine, Humans, CXCL10, Retrospective Studies, Hepatitis, business.industry, Infant, Retrospective cohort study, medicine.disease, digestive system diseases, Cross-Sectional Studies, 030104 developmental biology, DNA, Viral, Immunology, business, Biomarkers
Abstract

Contains fulltext : 215528.pdf (Publisher’s version ) (Open Access) Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-beta and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-beta and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.

Published
2019

14. Genome-wide Interaction Analysis of Air Pollution Exposure and Childhood Asthma with Functional Follow-up

Author

Gref, Anna, Kebede Merid, Simon, Gruzieva, Olena, Ballereau, Stéphane, Becker, Allan, Bellander, Tom, Bergström, Anna, Bossé, Yohan, Bottai, Matteo, Chan-Yeung, Moira, Fuertes, Elaine, Ierodiakonou, Despo, Jiang, Ruiwei, Joly, Stéphane, Jones, Meaghan, Kobor, Michael S, Korek, Michal, Kozyrskyj, Anita L, Kumar, Ashish, Lemonnier, Nathanaël, MacIntyre, Elaina, Ménard, Camille, Nickle, David, Obeidat, Ma'en, Pellet, Johann, Standl, Marie, Sääf, Annika, Söderhäll, Cilla, Tiesler, Carla Mt, van den Berge, Maarten, Vonk, Judith M, Vora, Hita, Xu, Cheng-Jian, Antó, Josep M, Auffray, Charles, Brauer, Michael, Bousquet, Jean, Brunekreef, Bert, Gauderman, W James, Heinrich, Joachim, Kere, Juha, Koppelman, Gerard H, Postma, Dirkje, Carlsten, Christopher, Pershagen, Göran, Melén, Erik, dIRAS RA-2, Risk Assessment, LS IRAS EEPI ME (Milieu epidemiologie), Dep IRAS, dIRAS RA-2, Risk Assessment, LS IRAS EEPI ME (Milieu epidemiologie), Dep IRAS, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, 0301 basic medicine, Air pollution exposure, Respiratory System, Critical Care and Intensive Care Medicine, ASSOCIATION SCANS, 0302 clinical medicine, expression quantitative trait locus, Gene–environment interaction, Child, GENE-ENVIRONMENT INTERACTION, Vehicle Emissions, Genetics, DIESEL EXHAUST, genome-wide interaction study, BIRTH COHORT, LARGE-SCALE, ESCAPE PROJECT, 11 Medical And Health Sciences, TOBACCO-SMOKE EXPOSURE, Europe, LUNG-FUNCTION, Genome-wide Interaction Study, Methylation, Gene Expression, Expression Quantitative Trait Locus, Children, Female, Birth cohort, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, Land use regression, eQTL, Polymorphism, Single Nucleotide, OBSTRUCTIVE PULMONARY-DISEASE, 03 medical and health sciences, Critical Care Medicine, children, General & Internal Medicine, Air Pollution, Environmental health, medicine, Humans, SNP, LAND-USE REGRESSION, Asthma, Childhood asthma, Science & Technology, business.industry, Original Articles, medicine.disease, 030104 developmental biology, 030228 respiratory system, North America, Expression quantitative trait loci, gene expression, methylation, business, Follow-Up Studies
Abstract

Rationale: The evidence supporting an association between traffic related air pollution exposure and incident childhood asthma is inconsistent and may depend on genetic factors.Objectives: To identify gene-environment interaction effects on childhood asthma using genome-wide single-nucleotide polymorphism (SNP) data and air pollution exposure. Identified loci were further analyzed at epigenetic and transcriptomic levels.Methods: We used land use regression models to estimate individual air pollution exposure (represented by outdoor NO2 levels) at the birth address and performed a genome-wide interaction study for doctors' diagnoses of asthma up to 8 years in three European birth cohorts (n = 1,534) with look-up for interaction in two separate North American cohorts, CHS (Children's Health Study) and CAPPS/SAGE (Canadian Asthma Primary Prevention Study/Study of Asthma, Genetics and Environment) (n = 1,602 and 186 subjects, respectively). We assessed expression quantitative trait locus effects in human lung specimens and blood, as well as associations among, air pollution exposure, methylation, and transcriptomic patterns.Measurements and Main Results: In the European cohorts, 186 SNPs had an interaction P Conclusions: Our results indicated that gene-environment interactions are important for asthma development and provided supportive evidence for interaction with air pollution for ADCY2, B4GALT5, and DLG2.

Published
2017

15. The emerging landscape of dynamic DNA methylation in early childhood

Author

Xu, Cheng-Jian, Bonder, Marc Jan, Söderhäll, Cilla, Bustamante, Mariona, Baïz, Nour, Gehring, Ulrike, Jankipersadsing, Soesma A, Van Der Vlies, Pieter, van Diemen, Cleo C, van Rijkom, Bianca, Just, Jocelyne, Kull, Inger, Kere, Juha, Antó, Josep Maria, Bousquet, Jean, Zhernakova, Alexandra, Wijmenga, Cisca, Annesi-Maesano, Isabella, Sunyer, Jordi, Melén, Erik, Li, Yang, Postma, Dirkje S, Koppelman, Gerard H, LS IRAS EEPI ME (Milieu epidemiologie), dIRAS RA-2, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de l'Asthme et des Allergies [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Research Programs Unit, Juha Kere / Principal Investigator, LS IRAS EEPI ME (Milieu epidemiologie), dIRAS RA-2, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Epigenomics, 0301 basic medicine, Aging, Methylation quatitative trait loci, ADN, DISEASE, Methylation quantitative trait loci, Epigenesis, Genetic, Child Development, Pregnancy, Non-U.S. Gov't, Child, POPULATION, Maternal smoking, Genetics, DNA methylation, NEWBORNS, Research Support, Non-U.S. Gov't, Smoking, 1184 Genetics, developmental biology, physiology, Environmental exposure, Methylation, 3. Good health, D-ASPARTATE, Maternal Exposure, Child, Preschool, Prenatal Exposure Delayed Effects, Female, Metilació, PROJECT, Research Article, Infància, Biotechnology, Quantitative Trait Loci, Genomics, Quantitative trait locus, Biology, Research Support, 03 medical and health sciences, AGE, Genetic, MICROARRAY, Journal Article, Humans, Genetic Predisposition to Disease, COHORT, Epigenetics, Preschool, Gene, METAANALYSIS, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Infant, Newborn, Genetic Variation, Infant, DNA, DNA Methylation, Newborn, Childhood, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, ASTHMA, CpG Islands, 3111 Biomedicine, Epigenesis, Genome-Wide Association Study
Abstract

Background: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood. Results: By analysing 538 paired DNA blood samples from children at birth and at 4–5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p

Published
2017
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16. Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking

Author

Sikdar, Sinjini, Joehanes, Roby, Joubert, Bonnie R, Xu, Cheng-Jian, Vives-Usano, Marta, Rezwan, Faisal I, Felix, Janine F, Ward, James M, Guan, Weihua, Richmond, Rebecca C, Brody, Jennifer A, Küpers, Leanne K, Baïz, Nour, Håberg, Siri E, Smith, Jennifer A, Reese, Sarah E, Aslibekyan, Stella, Hoyo, Cathrine, Dhingra, Radhika, Markunas, Christina A, Xu, Tao, Reynolds, Lindsay M, Just, Allan C, Mandaviya, Pooja R, Ghantous, Akram, Bennett, Brian D, Wang, Tianyuan, Consortium, The Bios, Bakulski, Kelly M, Melen, Erik, Zhao, Shanshan, Jin, Jianping, Herceg, Zdenko, Meurs, Joyce Van, Taylor, Jack A, Baccarelli, Andrea A, Murphy, Susan K, Liu, Yongmei, Munthe-Kaas, Monica Cheng, Deary, Ian J, Nystad, Wenche, Waldenberger, Melanie, Annesi-Maesano, Isabella, Conneely, Karen, Jaddoe, Vincent Wv, Arnett, Donna, Snieder, Harold, Kardia, Sharon Lr, Relton, Caroline L, Ong, Ken K, Ewart, Susan, Moreno-Macias, Hortensia, Romieu, Isabelle, Sotoodehnia, Nona, Fornage, Myriam, Motsinger-Reif, Alison, Koppelman, Gerard H, Bustamante, Mariona, Levy, Daniel, and London, Stephanie J

Subjects
Adult, Epigenomics, epigenetics, Infant, Newborn, cigarette smoking, DNA Methylation, infant, 3. Good health, Epigenesis, Genetic, Cohort Studies, Maternal Exposure, Pregnancy, Prenatal Exposure Delayed Effects, Tobacco Smoking, Humans, CpG Islands, Female, methylation
Abstract

Aim: 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 in utero exposure in newborns is unknown. Materials & methods: 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). Results & conclusion: 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.

17. DNA methylation in childhood asthma

Author

Mariona Bustamante, Francesco Forastiere, Henriette A. Smit, Petter Mowinckel, Marjan Kerkhof, Tari Haahtela, Martijn C. Nawijn, Raul Aguirre-Gamboa, Dan Mason, Mihai G. Netea, Cisca Wijmenga, Raf Azad, Vegard Hovland, John Wright, Josep M. Antó, Cilla Söderhäll, Pieter van der Vlies, William O.C.M. Cookson, Bianca van Rijkom, Lovisa E. Reinius, Soesma A Jankipersadsing, Leda Chatzi, Nour Baïz, Erik Melén, Daniela Porta, Olena Gruzieva, Juha Kere, Isabella Annesi-Maesano, Maties Torrent, Charles Auffray, Cleo C. van Diemen, Manolis Kogevinas, Davide Gori, Johann Pellet, Jose Ramon Bilbao, Harri Alenius, Göran Pershagen, Sabrina Llop, Miriam F. Moffatt, Nathanaël Lemonnier, Ashok Kumar, Simon Kebede Merid, Nanna Fyhrquist, Stephane Ballereau, Tiina Laatikainen, Cheng-Jian Xu, Johan C. de Jongste, Marc Jan Bonder, Judith Garcia-Aymerich, Karin C. Lødrup Carlsen, J Sunyer, Mikel Basterrechea, Dario Greco, Yang Li, Jean Bousquet, Ulrike Gehring, Catherine Laprise, Maria Pia Fantini, Rosemary R. C. McEachan, Bert Brunekreef, Stefano Guerra, Gerard H. Koppelman, Cornelis J. Vermeulen, Andréanne Morin, Carmen Iñiguez, Kai-Håkon Carlsen, Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, CIBER de Epidemiología y Salud Pública (CIBERESP), IMIM-Hospital del Mar, Generalitat de Catalunya, Universitat Pompeu Fabra [Barcelona] (UPF), Karolinska Institutet [Stockholm], University of Helsinki, King‘s College London, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Stockholm County Council, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Keck School of Medicine [Los Angeles], University of Southern California (USC), Azienda Sanitaria Locale [ROMA] (ASL), McGill University and Genome Quebec Innovation Centre, Département des Sciences Fondamentales [Chicoutimi] (DSF), Université du Québec à Chicoutimi (UQAC), European Institute for Systems Biology and Medicine (EISBM), Arizona Respiratory Center, Radboud University Medical Center [Nijmegen], Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Department of Dermatology, Allergology and Venereology, Clinicum, Medicum, Department of Bacteriology and Immunology, HUS Inflammation Center, One Health Chemisch, dIRAS RA-2, Pediatrics, RS: NUTRIM - R3 - Respiratory & Age-related Health, Complexe Genetica, RS: NUTRIM - R4 - Gene-environment interaction, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Xu, Cheng-Jian, Söderhäll, Cilla, Bustamante, Mariona, Baïz, Nour, Gruzieva, Olena, Gehring, Ulrike, Mason, Dan, Chatzi, Leda, Basterrechea, Mikel, Llop, Sabrina, Torrent, Matie, Forastiere, Francesco, Fantini, Maria Pia, Carlsen, Karin C Lødrup, Haahtela, Tari, Morin, Andréanne, Kerkhof, Marjan, Merid, Simon Kebede, van Rijkom, Bianca, Jankipersadsing, Soesma A., Bonder, Marc Jan, Ballereau, Stephane, Vermeulen, Cornelis J., Aguirre-Gamboa, Raul, de Jongste, Johan C., Smit, Henriette A., Kumar, Ashish, Pershagen, Göran, Guerra, Stefano, Garcia-Aymerich, Judith, Greco, Dario, Reinius, Lovisa, McEachan, Rosemary R.C., Azad, Raf, Hovland, Vegard, Mowinckel, Petter, Alenius, Harri, Fyhrquist, Nanna, Lemonnier, Nathanaël, Pellet, Johann, Auffray, Charle, van der Vlies, Pieter, van Diemen, Cleo C., Li, Yang, Wijmenga, Cisca, Netea, Mihai G., Moffatt, Miriam F., Cookson, William O.C.M., Anto, Josep M., Bousquet, Jean, Laatikainen, Tiina, Laprise, Catherine, Carlsen, Kai-Håkon, Gori, Davide, Porta, Daniela, Iñiguez, Carmen, Bilbao, Jose Ramon, Kogevinas, Manoli, Wright, John, Brunekreef, Bert, Kere, Juha, Nawijn, Martijn C., Annesi-Maesano, Isabella, Sunyer, Jordi, Melén, Erik, and Koppelman, Gerard H.

Subjects
Male, 0301 basic medicine, Allergy, Cytotoxic, T-Lymphocytes, [SDV]Life Sciences [q-bio], Respiratory System, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], CHILDREN, Immunoglobulin E, Epigenesis, Genetic, Child, POPULATION, education.field_of_study, biology, Methylation, 3. Good health, CpG site, Child, Preschool, DNA methylation, Female, BIOS Consortium, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, Population, PHENOTYPES, IMMUNITY, 03 medical and health sciences, Critical Care Medicine, Genetic, General & Internal Medicine, medicine, Humans, COHORT, Epigenetics, IGE, EXPOSURE, Preschool, education, Asthma, Science & Technology, business.industry, RHINITIS, DNA, DNA Methylation, medicine.disease, Eosinophils, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Immunology, biology.protein, GENOMEWIDE ASSOCIATION, CpG Islands, business, COLLECTION, T-Lymphocytes, Cytotoxic, Epigenesis, Genome-Wide Association Study
Abstract

Background: DNA methylation profiles associated with childhood asthma might provide novel insights into disease pathogenesis. We did an epigenome-wide association study to assess methylation profiles associated with childhood asthma. Methods: We did a large-scale epigenome-wide association study (EWAS) within the Mechanisms of the Development of ALLergy (MeDALL) project. We examined epigenome-wide methylation using Illumina Infinium Human Methylation450 BeadChips (450K) in whole blood in 207 children with asthma and 610 controls at age 4–5 years, and 185 children with asthma and 546 controls at age 8 years using a cross-sectional case-control design. After identification of differentially methylated CpG sites in the discovery analysis, we did a validation study in children (4–16 years; 247 cases and 2949 controls) from six additional European cohorts and meta-analysed the results. We next investigated whether replicated CpG sites in cord blood predict later asthma in 1316 children. We subsequently investigated cell-type-specific methylation of the identified CpG sites in eosinophils and respiratory epithelial cells and their related gene-expression signatures. We studied cell-type specificity of the asthma association of the replicated CpG sites in 455 respiratory epithelial cell samples, collected by nasal brushing of 16-year-old children as well as in DNA isolated from blood eosinophils (16 with asthma, eight controls [age 2–56 years]) and compared this with whole-blood DNA samples of 74 individuals with asthma and 93 controls (age 1–79 years). Whole-blood transcriptional profiles associated with replicated CpG sites were annotated using RNA-seq data of subsets of peripheral blood mononuclear cells sorted by fluorescence-activated cell sorting. Findings: 27 methylated CpG sites were identified in the discovery analysis. 14 of these CpG sites were replicated and passed genome-wide significance (p

Published
2018
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18. Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking

Author

Harold Snieder, Stella Aslibekyan, Myriam Fornage, Erik Melén, Sinjini Sikdar, Jennifer A. Brody, Tianyuan Wang, Isabelle Romieu, Tao Xu, Ken K. Ong, Jack A. Taylor, Jennifer A. Smith, Daniel Levy, Radhika Dhingra, Sarah E. Reese, Christina A. Markunas, Susan K. Murphy, Cathrine Hoyo, Marta Vives-Usano, Bonnie R. Joubert, Mariona Bustamante, Faisal I. Rezwan, Isabella Annesi-Maesano, Brian D. Bennett, Caroline L Relton, Melanie Waldenberger, Andrea A. Baccarelli, Karen N. Conneely, Nona Sotoodehnia, Yongmei Liu, Siri E. Håberg, Susan Ewart, Akram Ghantous, Monica Cheng Munthe-Kaas, Wenche Nystad, Vincent W. V. Jaddoe, Rebecca C Richmond, Allan C. Just, Kelly M. Bakulski, Sharon L.R. Kardia, Weihua Guan, Roby Joehanes, Stephanie J. London, Donna K. Arnett, Leanne K. Küpers, Nour Baïz, Lindsay M. Reynolds, Hortensia Moreno-Macias, Alison A. Motsinger-Reif, Shanshan Zhao, James M. Ward, Pooja R. Mandaviya, Cheng-Jian Xu, Janine F. Felix, Ian J. Deary, Jianping Jin, Gerard H. Koppelman, Joyce B. J. van Meurs, Zdenko Herceg, Joehanes, Roby [0000-0001-5549-9054], Xu, Cheng-Jian [0000-0003-1586-4672], Wang, Tianyuan [0000-0002-3970-0771], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Groningen Research Institute for Asthma and COPD (GRIAC), Epidemiology, Erasmus MC other, Pediatrics, Clinical Chemistry, and Internal Medicine

Subjects
0301 basic medicine, Adult, Epigenomics, Cancer Research, Nutrition and Disease, Offspring, Physiology, cigarette smoking, Biology, Epigenesis, Genetic, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Voeding en Ziekte, maternal exposure, Genetics, medicine, Tobacco Smoking, Humans, 030212 general & internal medicine, Epigenetics, Prenatal exposure, epigenetics, Infant, Newborn, Cigarette Smoking, Infant, Maternal Exposure, Methylation, DNA Methylation, medicine.disease, infant, 3. Good health, 030104 developmental biology, In utero, Prenatal Exposure Delayed Effects, DNA methylation, CpG Islands, Female, ICEP, methylation, Research Article
Abstract

Aim: 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 in utero exposure in newborns is unknown. Materials & methods: 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). Results & conclusion: 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.

Published
2019
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19. Mechanisms of the Development of Allergy (MeDALL) : Introducing novel concepts in allergy phenotypes

Author

Isabelle Pin, Stefano Guerra, Cynthia Hohmann, Marit Westman, Mariona Pinart, Jordi Mestres, Martijn C. Nawijn, Tari Haahtela, Dirkje S. Postma, Torsten Zuberbier, Kalus Wenzel, Mika J. Mäkelä, Fanny Rancière, Karin C. Lødrup Carlsen, Mirela Curin, Dieter Maier, Stephane Ballereau, Johan Pellet, Cezmi A. Akdis, Claus Bachert, Erik Melén, Emilie Burte, Bénédicte Jacquemin, Jean Bousquet, Anne Cambon-Thomsen, Christian Lupinek, I. Skrindo, Mübeccel Akdis, Rachel Nadif, Bert Brunekreef, Judith Garcia-Aymerich, Jonathan M. Coquet, Valérie Siroux, Inger Kull, Peter Mowinckel, Bart N. Lambrecht, Renata Kiss, Anna Bedbrook, Ferran Ballester, Kai-Håkon Carlsen, Yvan Saeys, Raphaëlle Varraso, Emmanuelle Rial-Sebbag, Giuseppe De Carlo, Sibylle Koletzko, Maria Pia Fantini, Joachim Heinrich, Jordi Sunyer, Andrea von Berg, Gerard H. Koppelman, Theresa Keller, Vergard Hovland, John Wright, Nicolas Lemonnier, Josep M. Antó, Marta Benet, Rudolf Valenta, Irina Lehmann, Susanne Lau, Francesco Forastiere, Isabelle Momas, Niklas Andersson, Albert Arno, Pascal Demoly, Jocelyne Just, Anna Bergström, Charles Auffray, Henriette A. Smit, Delphine Smagghe, Manolis Kogevinas, Anna Asarnoj, Marie Standl, Daniela Porta, I. Annesi-Maesano, Martijn J. Schuijs, Ulrike Gehring, Mathies Torrent, Thomas Keil, Christina Tischer, Cheng-Jian Xu, Esben Eller, Marek L. Kowalski, Carsten Bindslev-Jensen, Leda Chatzi, Magnus Wickman, Natalia Ballardini, Leena von Hertzen, Xavier Basagaña, Anto, Josep M., Bousquet, Jean, Akdis, Mubeccel, Auffray, Charle, Keil, Thoma, Momas, Isabelle, Postma, Dirkje S., Valenta, Rudolf, Wickman, Magnu, Cambon-Thomsen, Anne, Haahtela, Tari, Lambrecht, Bart N., Lodrup Carlsen, Karin C., Koppelman, Gerard H., Sunyer, Jordi, Zuberbier, Torsten, Annesi-Maesano, Isabelle, Arno, Albert, Bindslev-Jensen, Carsten, De Carlo, Giuseppe, Forastiere, Francesco, Heinrich, Joachim, Kowalski, Marek L., Maier, Dieter, Melén, Erik, Smit, Henriette A., Standl, Marie, Wright, John, Asarnoj, Anna, Benet, Marta, Ballardini, Natalia, Garcia-Aymerich, Judith, Gehring, Ulrike, Guerra, Stefano, Hohmann, Cynthia, Kull, Inger, Lupinek, Christian, Pinart, Mariona, Skrindo, Ingebjorg, Westman, Marit, Smagghe, Delphine, Akdis, Cezmi, Andersson, Nikla, Bachert, Clau, Ballereau, Stephane, Ballester, Ferran, Basagana, Xavier, Bedbrook, Anna, Bergstrom, Anna, von Berg, Andrea, Brunekreef, Bert, Burte, Emilie, Carlsen, Kai-Hakon, Chatzi, Leda, Coquet, Jonathan M., Curin, Mirela, Demoly, Pascal, Eller, Esben, Fantini, Maria Pia, von Hertzen, Leena, Hovland, Vergard, Jacquemin, Benedicte, Just, Jocelyne, Keller, Theresa, Kiss, Renata, Kogevinas, Manoli, Koletzko, Sibylle, Lau, Susanne, Lehmann, Irina, Lemonnier, Nicola, Mäkelä, Mika, Mestres, Jordi, Mowinckel, Peter, Nadif, Rachel, Nawijn, Martijn C., Pellet, Johan, Pin, Isabelle, Porta, Daniela, Rancière, Fanny, Rial-Sebbag, Emmanuelle, Saeys, Yvan, Schuijs, Martijn J., Siroux, Valerie, Tischer, Christina G., Torrent, Mathie, Varraso, Raphaelle, Wenzel, Kalu, Xu, Cheng-Jian, dIRAS RA-2, LS IRAS EEPI ME (Milieu epidemiologie), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), European Institute for Systems Biology and Medicine (EISBM), Epidémiologie Environnementale : Impact Sanitaire des Pollutions (EA 4064), Université Paris Descartes - Paris 5 (UPD5), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins (DS3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre de l'Asthme et des Allergies [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut Albert Bonniot, Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
0301 basic medicine, Allergy, Genome-wide association study, Comorbidity, Immunoglobulin E, medicine.disease_cause, Cohort Studies, Translational Research, Biomedical, 0302 clinical medicine, Allergen, REGULATORY B-CELLS, PRECISION MEDICINE, Medicine, BIRTH COHORT INFANTS, ATOPIC-DERMATITIS, Immunology and Allergy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Child, media_common, biology, atopic dermatitis, Atopic dermatitis, 3. Good health, Europe, Multicenter Study, CHRONIC RESPIRATORY-DISEASES, rhiniti, Phenotype, INNER-CITY CHILDREN, Biomarker (medicine), Female, atopic dermatiti, Adolescent, EUROPEAN INNOVATION PARTNERSHIP, Immunology, review, 03 medical and health sciences, EARLY-LIFE, Young Adult, rhinitis, Asthma, Atopic Dermatitis, Rhinitis, Hypersensitivity, Journal Article, media_common.cataloged_instance, Animals, Humans, European union, MOUNTAIN CEDAR POLLINOSIS, business.industry, Gene Expression Profiling, CHILDHOOD ASTHMA, Allergens, medicine.disease, allergy, 030104 developmental biology, 030228 respiratory system, biology.protein, Immunization, business, Genome-Wide Association Study
Abstract

Asthma, rhinitis, and eczema are complex diseases with multiple genetic and environmental factors interlinked through IgE-associated and non–IgE-associated mechanisms. Mechanisms of the Development of ALLergy (MeDALL; EU FP7-CP-IP; project no: 261357; 2010-2015) studied the complex links of allergic diseases at the clinical and mechanistic levels by linking epidemiologic, clinical, and mechanistic research, including invivo and invitro models. MeDALL integrated 14 European birth cohorts, including 44,010 participants and 160 cohort follow-ups between pregnancy and age 20years. Thirteen thousand children were prospectively followed after puberty by using a newly standardized MeDALL Core Questionnaire. Amicroarray developed for allergen molecules with increased IgE sensitivity was obtained for 3,292 children. Estimates of air pollution exposure from previous studies were available for 10,000 children. Omics data included those from historical genome-wide association studies (23,000 children) and DNA methylation (2,173), targeted multiplex biomarker (1,427), andtranscriptomic (723) studies. Using classical epidemiology and machine-learning methods in 16,147 children aged 4years and 11,080 children aged 8years, MeDALL showed the multimorbidity of eczema, rhinitis, and asthma and estimated that only 38% of multimorbidity was attributable to IgE sensitization. MeDALL has proposed a new vision of multimorbidity independent of IgE sensitization, and has shown that monosensitization and polysensitization represent 2 distinct phenotypes. The translational component of MeDALL is shown by the identification of a novel allergic phenotype characterized by polysensitization and multimorbidity, which is associated with the frequency, persistence, and severity of allergic symptoms. The results of MeDALL will help integrate personalized, predictive, preventative, and participatory approaches in allergic diseases.

Published
2017
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