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7. Developmental determinants in non-communicable chronic diseases and ageing

Author

Bousquet, J, Anto, J M, Berkouk, K, Gergen, P, Antunes, J Pinto, Augé, P, Camuzat, T, Bringer, J, Mercier, J, Best, N, Bourret, R, Akdis, M, Arshad, S H, Bedbrook, A, Berr, C, Bush, A, Cavalli, G, Charles, M A, Clavel-Chapelon, F, Gillman, M, Gold, D R, Goldberg, M, Holloway, J W, Iozzo, P, Jacquemin, S, Jeandel, C, Kauffmann, F, Keil, T, Koppelman, G H, Krauss-Etschmann, S, Kuh, D, Lehmann, S, Carlsen, K C Lodrup, Maier, D, Méchali, M, Melén, E, Moatti, J P, Momas, I, Nérin, P, Postma, D S, Ritchie, K, Robine, J M, Samolinski, B, Siroux, V, Slagboom, P E, Smit, H A, Sunyer, J, Valenta, R, Van de Perre, P, Verdier, J M, Vrijheid, M, Wickman, M, Yiallouros, P, and Zins, M

Published
2015
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14. EAACI position statement on asthma exacerbations and severe asthma

Author

Custovic, A., Johnston, S. L., Pavord, I., Gaga, M., Fabbri, L., Bel, E. H., Le Souëf, P., Lötvall, J., Demoly, P., Akdis, C. A., Ryan, D., Mäkelä, M. J., Martinez, F., Holloway, J. W., Saglani, S., OʼByrne, P., Papi, A., Sergejeva, S., Magnan, A., Del Giacco, S., Kalayci, O., Hamelmann, E., and Papadopoulos, N. G.

Published
2013
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15. Role of DNA methylation in the association of lung function with body mass index:a two-step epigenetic Mendelian randomisation study

Author

Amaral, A. F. (André F. S.), Imboden, M. (Medea), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Minelli, C. (Cosetta), Garcia-Aymerich, J. (Judith), Peralta, G. P. (Gabriela P.), Auvinen, J. (Juha), Jeong, A. (Ayoung), Schaffner, E. (Emmanuel), Beckmeyer-Borowko, A. (Anna), Holloway, J. W. (John W.), Jarvelin, M.-R. (Marjo-Riitta), Probst-Hensch, N. M. (Nicole M.), Jarvis, D. L. (Deborah L.), and f. t. (for the ALEC consortium)

Subjects
DNA methylation, Effect mediation, Mendelian randomisation, Body mass index, Lung function
Abstract

Background: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation. Methods: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV₁, FVC, and FEV₁/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic

Published
2020

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

Author

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

Abstract

Background: DNA 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. Methods: We 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. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10⁻⁷, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10⁻⁴; adolescence Penrichment = 2.10 × 10⁻⁷). Conclusions: There were only minimal associations of DNA methylation with childhood and adol

Published
2020

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

Author

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

Abstract

Background: Preterm 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. Methods: We 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. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P < 1.06 × 10⁻⁷, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020

20. Genome-wide association study to identify genetic determinants of severe asthma

Author

Wan, Y I, Shrine, N R G, Soler Artigas, M, Wain, L V, Blakey, J D, Moffatt, M F, Bush, A, Chung, K F, Cookson, W O C M, Strachan, D P, Heaney, L, Al-Momani, B A H, Mansur, A H, Manney, S, Thomson, N C, Chaudhuri, R, Brightling, C E, Bafadhel, M, Singapuri, A, Niven, R, Simpson, A, Holloway, J W, Howarth, P H, Hui, J, Musk, A W, James, A L, Brown, M A, Baltic, S, Ferreira, M A R, Thompson, P J, Tobin, M D, Sayers, I, and Hall, I P

Published
2012
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30. Functional Translation of IL33 Locus Polymorphisms Into Altered Epithelial Cell Function Underlying Asthma

Author

Ketelaar, M., Portelli, M. A., Dijk, F. N., Faiz, A., Shrine, N., Hankinson, J., Bhaker, S., Henry, A. P., Billington, C. K., Shaw, D., Johnson, S. R., Benest, A. V., Pogson, Z. E. K., Fogarty, A., McKeever, T. M., Singapuri, A., Heaney, L., Mansur, A., Gaudhuri, R., Thomson, N. C., Holloway, J. W., Lockett, G. A., Howarth, P. H., Niven, R., Simpson, A., Tobin, M. D., Postma, D. S., Hall, I. P., Wain, L. V., Brightling, C. E., Obeidat, M., Sin, D. D., van den Berge, M., Koppelman, G. H., Sayers, I., Nawijn, M. C., and Groningen Research Institute for Asthma and COPD (GRIAC)

Published
2019

31. Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Author

Reese, S. E. (Sarah E.), Xu, C.-J. (Cheng-Jian), den Dekker, H. T. (Herman T.), Lee, M. K. (Mi Kyeong), Sikdar, S. (Sinjini), Ruiz-Arenas, C. (Carlos), Merid, S. K. (Simon K.), Rezwan, F. I. (Faisal I.), Page, C. M. (Christian M.), Ullemar, V. (Vilhelmina), Melton, P. E. (Phillip E.), Oh, S. S. (Sam S.), Yang, I. V. (Ivana V.), Burrows, K. (Kimberley), Söderhäll, C. (Cilla), Jima, D. D. (Dereje D.), Gao, L. (Lu), Arathimos, R. (Ryan), Küpers, L. K. (Leanne K.), Wielscher, M. (Matthias), Rzehak, P. (Peter), Lahti, J. (Jari), Laprise, C. (Catherine), Madore, A.-M. (Anne-Marie), Ward, J. (James), Bennett, B. D. (Brian D.), Wang, T. (Tianyuan), Bell, D. A. (Douglas A.), T. B. (The BIOS consortium), Vonk, J. M. (Judith M.), Håberg, S. E. (Siri E.), Zhao, S. (Shanshan), Karlsson, R. (Robert), Hollams, E. (Elysia), Hu, D. (Donglei), Richards, A. J. (Adam J.), Bergström, A. (Anna), Sharp, G. C. (Gemma C.), Felix, J. F. (Janine F.), Bustamante, M. (Mariona), Gruzieva, O. (Olena), Maguire, R. L. (Rachel L.), Gilliland, F. (Frank), Baïz, N. (Nour), Nohr, E. A. (Ellen A.), Corpeleijn, E. (Eva), Sebert, S. (Sylvain), Karmaus, W. (Wilfried), Grote, V. (Veit), Kajantie, E. (Eero), Magnus, M. C. (Maria C.), Örtqvist, A. K. (Anne K.), Eng, C. (Celeste), Liu, A. H. (Andrew H.), Kull, I. (Inger), Jaddoe, V. W. (Vincent W.V.), Sunyer, J. (Jordi), Kere, J. (Juha), Hoyo, C. (Cathrine), Annesi-Maesano, I. (Isabella), Arshad, S. H. (Syed Hasan), Koletzko, B. (Berthold), Brunekreef, B. (Bert), Binder, E. B. (Elisabeth B.), Räikkönen, K. (Katri), Reischl, E. (Eva), Holloway, J. W. (John W.), Järvelin, M.-R. (Marjo-Riitta), Snieder, H. (Harold), Kazmi, N. (Nabila), Breton, C. V. (Carrie V.), Murphy, S. K. (Susan K.), Pershagen, G. (Göran), Anto, J. M. (Josep Maria), Relton, C. L. (Caroline L.), Schwartz, D. A. (David A.), Burchard, E. G. (Esteban G.), Huang, R.-C. (Rae-Chi), Nystad, W. (Wenche), Almqvist, C. (Catarina), Henderson, A. J. (A. John), Melén, E. (Erik), Duijts, L. (Liesbeth), Koppelman, G. H. (Gerard H.), and London, S. J. (Stephanie J.)

Subjects
epigenetics, newborn, methylation, asthma, drug development, childhood
Abstract

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Published
2019

39. Epigenome-wide association study of lung function level and its change

Author

Imboden, M. (Medea), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Amaral, A. F. (André F.S.), Schaffner, E. (Emmanuel), Jeong, A. (Ayoung), Beckmeyer-Borowko, A. (Anna), Harris, S. E. (Sarah E.), Starr, J. M. (John M.), Deary, I. J. (Ian J.), Flexeder, C. (Claudia), Waldenberger, M. (Melanie), Peters, A. (Annette), Schulz, H. (Holger), Chen, S. (Su), Sunny, S. K. (Shadia Khan), Karmaus, W. J. (Wilfried J.J.), Jiang, Y. (Yu), Erhart, G. (Gertraud), Kronenberg, F. (Florian), Arathimos, R. (Ryan), Sharp, G. C. (Gemma C.), Henderson, A. J. (Alexander John), Fu, Y. (Yu), Piirilä, P. (Päivi), Pietiläinen, K. H. (Kirsi H.), Ollikainen, M. (Miina), Johansson, A. (Asa), Gyllensten, U. (Ulf), de Vries, M. (Maaike), van der Plaat, D. A. (Diana A.), de Jong, K. (Kim), Boezen, H. M. (H. Marike), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), Jarvelin, M.-R. (Marjo-Riitta), Holloway, J. W. (John W.), Jarvis, D. (Deborah), Probst-Hensch, N. M. (Nicole M.), Imboden, M. (Medea), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Amaral, A. F. (André F.S.), Schaffner, E. (Emmanuel), Jeong, A. (Ayoung), Beckmeyer-Borowko, A. (Anna), Harris, S. E. (Sarah E.), Starr, J. M. (John M.), Deary, I. J. (Ian J.), Flexeder, C. (Claudia), Waldenberger, M. (Melanie), Peters, A. (Annette), Schulz, H. (Holger), Chen, S. (Su), Sunny, S. K. (Shadia Khan), Karmaus, W. J. (Wilfried J.J.), Jiang, Y. (Yu), Erhart, G. (Gertraud), Kronenberg, F. (Florian), Arathimos, R. (Ryan), Sharp, G. C. (Gemma C.), Henderson, A. J. (Alexander John), Fu, Y. (Yu), Piirilä, P. (Päivi), Pietiläinen, K. H. (Kirsi H.), Ollikainen, M. (Miina), Johansson, A. (Asa), Gyllensten, U. (Ulf), de Vries, M. (Maaike), van der Plaat, D. A. (Diana A.), de Jong, K. (Kim), Boezen, H. M. (H. Marike), Hall, I. P. (Ian P.), Tobin, M. D. (Martin D.), Jarvelin, M.-R. (Marjo-Riitta), Holloway, J. W. (John W.), Jarvis, D. (Deborah), and Probst-Hensch, N. M. (Nicole M.)

Abstract

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults. In a discovery–replication EWAS design, DNAme in blood and spirometry were measured twice, 6—15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10−7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers. EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10−21 and pcombined=7.22×10−50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10−20). Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-s

Published
2019

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

Author

Kupers, L. K. (Leanne K.), Monnereau, C. (Claire), Sharp, G. C. (Gemma C.), Yousefi, P. (Paul), Salas, L. A. (Lucas A.), Ghantous, A. (Akram), Page, C. M. (Christian M.), Reese, S. E. (Sarah E.), Wilcox, A. J. (Allen J.), Czamara, D. (Darina), Starling, A. P. (Anne P.), Novoloaca, A. (Alexei), Lent, S. (Samantha), Roy, R. (Ritu), Hoyo, C. (Cathrine), Breton, C. V. (Carrie, V), Allard, C. (Catherine), Just, A. C. (Allan C.), Bakulski, K. M. (Kelly M.), Holloway, J. W. (John W.), Everson, T. M. (Todd M.), Xu, C.-J. (Cheng-Jian), Huang, R.-C. (Rae-Chi), van der Plaat, D. A. (Diana A.), Wielscher, M. (Matthias), Merid, S. K. (Simon Kebede), Ullemar, V. (Vilhelmina), Rezwan, F. I. (Faisal, I), Lahti, J. (Jari), van Dongen, J. (Jenny), Langie, S. A. (Sabine A. S.), Richardson, T. G. (Tom G.), Magnus, M. C. (Maria C.), Nohr, E. A. (Ellen A.), Xu, Z. (Zongli), Duijts, L. (Liesbeth), Zhao, S. (Shanshan), Zhang, W. (Weiming), Plusquin, M. (Michelle), DeMeo, D. L. (Dawn L.), Solomon, O. (Olivia), Heimovaara, J. H. (Joosje H.), Jima, D. D. (Dereje D.), Gao, L. (Lu), Bustamante, M. (Mariona), Perron, P. (Patrice), Wright, R. O. (Robert O.), Hertz-Picciotto, I. (Irva), Zhang, H. (Hongmei), Karagas, M. R. (Margaret R.), Gehring, U. (Ulrike), Marsit, C. J. (Carmen J.), Beilin, L. J. (Lawrence J.), Vonk, J. M. (Judith M.), Jarvelin, M.-R. (Marjo-Riitta), Bergstrom, A. (Anna), Ortqvist, A. K. (Anne K.), Ewart, S. (Susan), Villa, P. M. (Pia M.), Moore, S. E. (Sophie E.), Willemsen, G. (Gonneke), Standaert, A. R. (Arnout R. L.), Haberg, S. E. (Siri E.), Sorensen, T. I. (Thorkild I. A.), Taylor, J. A. (Jack A.), Raikkonen, K. (Katri), Yang, I. V. (Ivana, V), Kechris, K. (Katerina), Nawrot, T. S. (Tim S.), Silver, M. J. (Matt J.), Gong, Y. Y. (Yun Yun), Richiardi, L. (Lorenzo), Kogevinas, M. (Manolis), Litonjua, A. A. (Augusto A.), Eskenazi, B. (Brenda), Huen, K. (Karen), Mbarek, H. (Hamdi), Maguire, R. L. (Rachel L.), Dwyer, T. (Terence), Vrijheid, M. (Martine), Bouchard, L. (Luigi), Baccarelli, A. A. (Andrea A.), Croen, L. A. (Lisa A.), Karmaus, W. (Wilfried), Anderson, D. (Denise), de Vries, M. (Maaike), Sebert, S. (Sylvain), Kere, J. (Juha), Karlsson, R. (Robert), Arshad, S. H. (Syed Hasan), Hamalainen, E. (Esa), Routledge, M. N. (Michael N.), Boomsma, D. I. (Dorret, I), Feinberg, A. P. (Andrew P.), Newschaffer, C. J. (Craig J.), Govarts, E. (Eva), Moisse, M. (Matthieu), Fallin, M. D. (M. Daniele), Melen, E. (Erik), Prentice, A. M. (Andrew M.), Kajantie, E. (Eero), Almqvist, C. (Catarina), Oken, E. (Emily), Dabelea, D. (Dana), Boezen, H. M. (H. Marike), Melton, P. E. (Phillip E.), Wright, R. J. (Rosalind J.), Koppelman, G. H. (Gerard H.), Trevisi, L. (Letizia), Hivert, M.-F. (Marie-France), Sunyer, J. (Jordi), Munthe-Kaas, M. C. (Monica C.), Murphy, S. K. (Susan K.), Corpeleijn, E. (Eva), Wiemels, J. (Joseph), Holland, N. (Nina), Herceg, Z. (Zdenko), Binder, E. B. (Elisabeth B.), Smith, G. D. (George Davey), Jaddoe, V. W. (Vincent W. V.), Lie, R. T. (Rolv T.), Nystad, W. (Wenche), London, S. J. (Stephanie J.), Lawlor, D. A. (Debbie A.), Relton, C. L. (Caroline L.), Snieder, H. (Harold), Felix, J. F. (Janine F.), Kupers, L. K. (Leanne K.), Monnereau, C. (Claire), Sharp, G. C. (Gemma C.), Yousefi, P. (Paul), Salas, L. A. (Lucas A.), Ghantous, A. (Akram), Page, C. M. (Christian M.), Reese, S. E. (Sarah E.), Wilcox, A. J. (Allen J.), Czamara, D. (Darina), Starling, A. P. (Anne P.), Novoloaca, A. (Alexei), Lent, S. (Samantha), Roy, R. (Ritu), Hoyo, C. (Cathrine), Breton, C. V. (Carrie, V), Allard, C. (Catherine), Just, A. C. (Allan C.), Bakulski, K. M. (Kelly M.), Holloway, J. W. (John W.), Everson, T. M. (Todd M.), Xu, C.-J. (Cheng-Jian), Huang, R.-C. (Rae-Chi), van der Plaat, D. A. (Diana A.), Wielscher, M. (Matthias), Merid, S. K. (Simon Kebede), Ullemar, V. (Vilhelmina), Rezwan, F. I. (Faisal, I), Lahti, J. (Jari), van Dongen, J. (Jenny), Langie, S. A. (Sabine A. S.), Richardson, T. G. (Tom G.), Magnus, M. C. (Maria C.), Nohr, E. A. (Ellen A.), Xu, Z. (Zongli), Duijts, L. (Liesbeth), Zhao, S. (Shanshan), Zhang, W. (Weiming), Plusquin, M. (Michelle), DeMeo, D. L. (Dawn L.), Solomon, O. (Olivia), Heimovaara, J. H. (Joosje H.), Jima, D. D. (Dereje D.), Gao, L. (Lu), Bustamante, M. (Mariona), Perron, P. (Patrice), Wright, R. O. (Robert O.), Hertz-Picciotto, I. (Irva), Zhang, H. (Hongmei), Karagas, M. R. (Margaret R.), Gehring, U. (Ulrike), Marsit, C. J. (Carmen J.), Beilin, L. J. (Lawrence J.), Vonk, J. M. (Judith M.), Jarvelin, M.-R. (Marjo-Riitta), Bergstrom, A. (Anna), Ortqvist, A. K. (Anne K.), Ewart, S. (Susan), Villa, P. M. (Pia M.), Moore, S. E. (Sophie E.), Willemsen, G. (Gonneke), Standaert, A. R. (Arnout R. L.), Haberg, S. E. (Siri E.), Sorensen, T. I. (Thorkild I. A.), Taylor, J. A. (Jack A.), Raikkonen, K. (Katri), Yang, I. V. (Ivana, V), Kechris, K. (Katerina), Nawrot, T. S. (Tim S.), Silver, M. J. (Matt J.), Gong, Y. Y. (Yun Yun), Richiardi, L. (Lorenzo), Kogevinas, M. (Manolis), Litonjua, A. A. (Augusto A.), Eskenazi, B. (Brenda), Huen, K. (Karen), Mbarek, H. (Hamdi), Maguire, R. L. (Rachel L.), Dwyer, T. (Terence), Vrijheid, M. (Martine), Bouchard, L. (Luigi), Baccarelli, A. A. (Andrea A.), Croen, L. A. (Lisa A.), Karmaus, W. (Wilfried), Anderson, D. (Denise), de Vries, M. (Maaike), Sebert, S. (Sylvain), Kere, J. (Juha), Karlsson, R. (Robert), Arshad, S. H. (Syed Hasan), Hamalainen, E. (Esa), Routledge, M. N. (Michael N.), Boomsma, D. I. (Dorret, I), Feinberg, A. P. (Andrew P.), Newschaffer, C. J. (Craig J.), Govarts, E. (Eva), Moisse, M. (Matthieu), Fallin, M. D. (M. Daniele), Melen, E. (Erik), Prentice, A. M. (Andrew M.), Kajantie, E. (Eero), Almqvist, C. (Catarina), Oken, E. (Emily), Dabelea, D. (Dana), Boezen, H. M. (H. Marike), Melton, P. E. (Phillip E.), Wright, R. J. (Rosalind J.), Koppelman, G. H. (Gerard H.), Trevisi, L. (Letizia), Hivert, M.-F. (Marie-France), Sunyer, J. (Jordi), Munthe-Kaas, M. C. (Monica C.), Murphy, S. K. (Susan K.), Corpeleijn, E. (Eva), Wiemels, J. (Joseph), Holland, N. (Nina), Herceg, Z. (Zdenko), Binder, E. B. (Elisabeth B.), Smith, G. D. (George Davey), Jaddoe, V. W. (Vincent W. V.), Lie, R. T. (Rolv T.), Nystad, W. (Wenche), London, S. J. (Stephanie J.), Lawlor, D. A. (Debbie A.), Relton, C. L. (Caroline L.), Snieder, H. (Harold), and Felix, J. F. (Janine F.)

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 < 1.06 x 10−7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10−74) and BMI in pregnancy (3/914, p = 1.13x10−3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.

Published
2019

41. GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI

Author

Alves, A. C. (Alexessander Couto), De Silva, N. M. (N. Maneka G.), Karhunen, V. (Ville), Sovio, U. (Ulla), Das, S. (Shikta), Taal, H. R. (H. Rob), Warrington, N. M. (Nicole M.), Lewin, A. M. (Alexandra M.), Kaakinen, M. (Marika), Cousminer, D. L. (Diana L.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Bond, T. A. (Tom A.), Lowry, E. (Estelle), Brown, C. D. (Christopher D.), Estivill, X. (Xavier), Lindi, V. (Virpi), Bradfield, J. P. (Jonathan P.), Geller, F. (Frank), Speed, D. (Doug), Coin, L. J. (Lachlan J. M.), Loh, M. (Marie), Barton, S. J. (Sheila J.), Beilin, L. J. (Lawrence J.), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Alili, R. (Rohia), Hatoum, I. J. (Ida J.), Schramm, K. (Katharina), Cartwright, R. (Rufus), Charles, M.-A. (Marie-Aline), Salerno, V. (Vincenzo), Clement, K. (Karine), Claringbould, A. A. (Annique A. J.), van Duijn, C. M. (Cornelia M.), Moltchanova, E. (Elena), Eriksson, J. G. (Johan G.), Elks, C. (Cathy), Feenstra, B. (Bjarke), Flexeder, C. (Claudia), Franks, S. (Stephen), Frayling, T. M. (Timothy M.), Freathy, R. M. (Rachel M.), Elliott, P. (Paul), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Hattersley, A. T. (Andrew T.), Rodriguez, A. (Alina), Banterle, M. (Marco), Heinrich, J. (Joachim), Heude, B. (Barbara), Holloway, J. W. (John W.), Hofman, A. (Albert), Hypponen, E. (Elina), Inskip, H. (Hazel), Kaplan, L. M. (Lee M.), Hedman, A. K. (Asa K.), Läärä, E. (Esa), Prokisch, H. (Holger), Grallert, H. (Harald), Lakka, T. A. (Timo A.), Lawlor, D. A. (Debbie A.), Melbye, M. (Mads), Ahluwalia, T. S. (Tarunveer S.), Marinelli, M. (Marcella), Millwood, I. Y. (Iona Y.), Palmer, L. J. (Lyle J.), Pennell, C. E. (Craig E.), Perry, J. R. (John R.), Ring, S. M. (Susan M.), Savolainen, M. J. (Markku J.), Rivadeneira, F. (Fernando), Standl, M. (Marie), Sunyer, J. (Jordi), Tiesler, C. M. (Carla M. T.), Uitterlinden, A. G. (Andre G.), Schierding, W. (William), O'Sullivan, J. M. (Justin M.), Prokopenko, I. (Inga), Herzig, K.-H. (Karl-Heinz), Smith, G. D. (George Davey), O'Reilly, P. (Paul), Felix, J. F. (Janine F.), Buxton, J. L. (Jessica L.), Blakemore, A. I. (Alexandra I. F.), Ong, K. K. (Ken K.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), Sebert, S. (Sylvain), McCarthy, M. I. (Mark I.), Jarvelin, M.-R. (Marjo-Riitta), Alves, A. C. (Alexessander Couto), De Silva, N. M. (N. Maneka G.), Karhunen, V. (Ville), Sovio, U. (Ulla), Das, S. (Shikta), Taal, H. R. (H. Rob), Warrington, N. M. (Nicole M.), Lewin, A. M. (Alexandra M.), Kaakinen, M. (Marika), Cousminer, D. L. (Diana L.), Thiering, E. (Elisabeth), Timpson, N. J. (Nicholas J.), Bond, T. A. (Tom A.), Lowry, E. (Estelle), Brown, C. D. (Christopher D.), Estivill, X. (Xavier), Lindi, V. (Virpi), Bradfield, J. P. (Jonathan P.), Geller, F. (Frank), Speed, D. (Doug), Coin, L. J. (Lachlan J. M.), Loh, M. (Marie), Barton, S. J. (Sheila J.), Beilin, L. J. (Lawrence J.), Bisgaard, H. (Hans), Bonnelykke, K. (Klaus), Alili, R. (Rohia), Hatoum, I. J. (Ida J.), Schramm, K. (Katharina), Cartwright, R. (Rufus), Charles, M.-A. (Marie-Aline), Salerno, V. (Vincenzo), Clement, K. (Karine), Claringbould, A. A. (Annique A. J.), van Duijn, C. M. (Cornelia M.), Moltchanova, E. (Elena), Eriksson, J. G. (Johan G.), Elks, C. (Cathy), Feenstra, B. (Bjarke), Flexeder, C. (Claudia), Franks, S. (Stephen), Frayling, T. M. (Timothy M.), Freathy, R. M. (Rachel M.), Elliott, P. (Paul), Widen, E. (Elisabeth), Hakonarson, H. (Hakon), Hattersley, A. T. (Andrew T.), Rodriguez, A. (Alina), Banterle, M. (Marco), Heinrich, J. (Joachim), Heude, B. (Barbara), Holloway, J. W. (John W.), Hofman, A. (Albert), Hypponen, E. (Elina), Inskip, H. (Hazel), Kaplan, L. M. (Lee M.), Hedman, A. K. (Asa K.), Läärä, E. (Esa), Prokisch, H. (Holger), Grallert, H. (Harald), Lakka, T. A. (Timo A.), Lawlor, D. A. (Debbie A.), Melbye, M. (Mads), Ahluwalia, T. S. (Tarunveer S.), Marinelli, M. (Marcella), Millwood, I. Y. (Iona Y.), Palmer, L. J. (Lyle J.), Pennell, C. E. (Craig E.), Perry, J. R. (John R.), Ring, S. M. (Susan M.), Savolainen, M. J. (Markku J.), Rivadeneira, F. (Fernando), Standl, M. (Marie), Sunyer, J. (Jordi), Tiesler, C. M. (Carla M. T.), Uitterlinden, A. G. (Andre G.), Schierding, W. (William), O'Sullivan, J. M. (Justin M.), Prokopenko, I. (Inga), Herzig, K.-H. (Karl-Heinz), Smith, G. D. (George Davey), O'Reilly, P. (Paul), Felix, J. F. (Janine F.), Buxton, J. L. (Jessica L.), Blakemore, A. I. (Alexandra I. F.), Ong, K. K. (Ken K.), Jaddoe, V. W. (Vincent W. V.), Grant, S. F. (Struan F. A.), Sebert, S. (Sylvain), McCarthy, M. I. (Mark I.), and Jarvelin, M.-R. (Marjo-Riitta)

Abstract

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the LEPR/LEPROT locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.

Published
2019

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

Author

Wiklund, P. (Petri), Karhunen, V. (Ville), Richmond, R. C. (Rebecca C.), Parmar, P. (Priyanka), Rodriguez, A. (Alina), De Silva, M. (Maneka), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Richardson, T. G. (Tom G.), Veijola, J. (Juha), Herzig, K.-H. (Karl-Heinz), Holloway, J. W. (John W.), Relton, C. L. (Caroline L.), Sebert, S. (Sylvain), Järvelin, M.-R. (Marjo-Riitta), Wiklund, P. (Petri), Karhunen, V. (Ville), Richmond, R. C. (Rebecca C.), Parmar, P. (Priyanka), Rodriguez, A. (Alina), De Silva, M. (Maneka), Wielscher, M. (Matthias), Rezwan, F. I. (Faisal I.), Richardson, T. G. (Tom G.), Veijola, J. (Juha), Herzig, K.-H. (Karl-Heinz), Holloway, J. W. (John W.), Relton, C. L. (Caroline L.), Sebert, S. (Sylvain), and Järvelin, M.-R. (Marjo-Riitta)

Abstract

Background: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. Methods: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. Results: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10⁻⁷) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. Conclusions: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

Published
2019

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