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1. The role of a parental history of Balkan endemic nephropathy in the occurrence of BEN: a prospective study

Author: Hanjangsit K, Karmaus W, Dimitrov P, Zhang H, Burch J, Tzolova S, and Batuman V
Subjects: Diseases of the genitourinary system. Urology, RC870-923
Abstract: Kesinee Hanjangsit1, Wilfried Karmaus1, Plamen Dimitrov2, Hongmei Zhang1, Jim Burch1, Svetla Tzolova2, Vecihi Batuman3,41Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC, USA; 2National Center of Public Health Protection, Sofia, Bulgaria; 3Section of Nephrology-Hypertension, Tulane University Medical Center, New Orleans, LA, USA; 4VA Medical Center, New Orleans, LA, USAAbstract: Balkan endemic nephropathy (BEN) is a chronic kidney disease that affects persons living in the Balkans. Despite the unique geographical specificity of this disease, its etiology has remained unclear. Even if a positive family history of BEN has been identified, it is still uncertain how the disease develops in offspring. In this paper, we examine clinical mechanisms related to the onset of BEN in individuals who have a parental history of BEN to identify early detection of the disease and formulate interventions. We conducted a 5-year prospective study, using markers in years one and three to predict new cases of BEN in year five. New cases of BEN were defined based on three criteria: parental history of BEN, reduced kidney size, and reduced kidney function. Incident cases were divided into (1) probable, (2) definite, and (3) combined labeled total incidence. We evaluated parental history in relation to BEN and tested the potentially intervening effects of kidney length, kidney cortex width, β2-microglobulin, C-reactive protein, and creatinine clearance, using path analyses. The findings of the path analyses suggested that parental history of BEN had both direct and indirect effects. The direct effect was significant for all three modes of parental history (biparental, maternal, and paternal; odds ratios 71.5, 52.3, and 50.1, respectively). The indirect effects of maternal BEN acted via kidney length and creatinine clearance. Biparental BEN was mediated by (1) kidney length and creatinine clearance, and (2) creatinine clearance alone. Paternal BEN had three indirect effects: (1) through kidney length and creatinine clearance, (2) via kidney cortex width and creatinine clearance, and (3) via kidney cortex width only. In conclusion, a family history of BEN led to reducedkidney length and cortex width, and a decline in creatinine clearance, which in turn predicted the onset of BEN.Keywords: Balkan endemic nephropathy, incidence of BEN, parental history of BEN, kidney size, β2-microglobulin, creatinine clearance
Published: 2012

2. Adjusting wheal size measures to correct atopy misclassification

Author: Zhang H, Karmaus W, Gan J, Bao W, Zhao YD, Rahardja D, Holloway JW, Scott M, and Arshad SH.
Subjects: Medicine (General), R5-920
Abstract: Hongmei Zhang1,*, Wilfried Karmaus1,*, Jianjun Gan2, Weichao Bao1,*, Yan D Zhao3, Dewi Rahardja3, John W Holloway5, Martha Scott4,5, Syed Hasan Arshad4,51Department of Epidemiology and Biostatistics, The University of South Carolina, Columbia, SC, USA; 2GlaxoSmithKline, Research Triangle Park, NC, USA; 3Department of Clinical Science and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA; 4The David Hide Asthma and Allergy Research Center, St Mary’s Hospital, Newport, Isle of Wight, UK; 5School of Medicine, University of Southampton, Southampton, UK *These authors contributed equally to this articlePurpose: Skin prick testing (SPT) is fundamental to the practice of clinical allergy identifying relevant allergens and predicting the clinical expression of disease. Wheal sizes on SPT are used to identify atopic cases, and the cut-off value for a positive test is commonly set at 3 mm. However, the measured wheal sizes do not solely reflect the magnitude of skin reaction to allergens, but also skin reactivity (reflected in the size of histamine reaction) and other random or non-random factors. We sought to estimate wheal sizes exclusively due to skin response to allergens and propose gender-specific cutoff points of atopy.Methods: We developed a Bayesian method to adjust observed wheal sizes by excluding histamine and other factor effects, based on which revised cutoff points are proposed for males and females, respectively. The method is then applied to and intensively evaluated using a study population aged 18, at a location on the Isle of Wight in the United Kingdom. To evaluate the proposed approach, two sample t-tests for population means and proportion tests are applied.Results: Four common aeroallergens, house dust mite (HDM), grass pollen, dog dander, and alternaria are considered in the study. Based on 3 mm cutoff, males tend to be more atopic than females (P-values are between 0.00087 and 0.062). After applying the proposed methods to adjust wheal sizes, our findings suggest that misclassifications of atopy occur more often in males. Revised allergen-specific cutoff values are proposed for each gender.Conclusion: To reduce the gender discrepancy, we may have two potentially convenient solutions. One way is to apply allergen-specific and gender-specific cutoff values following the proposed method. Alternatively, we can revise the concentration of allergens in the SPT solutions but keep the cutoff values unchanged, which may be more convenient to clinicians.Keywords: SPT, atopy, Bayesian method, joint modeling, misclassification
Published: 2011

3. A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Author: Li, S., Spitz, N., Ghantous, A., Abrishamcar, S., Reimann, B., Marques, I., Silver, M.J., Aguilar-Lacasaña, S., Kitaba, N., Rezwan, F.I., Röder, Stefan, Sirignano, L., Tuhkanen, J., Mancano, G., Sharp, G.C., Metayer, C., Morimoto, L., Stein, D.J., Zar, H.J., Alfano, R., Nawrot, T., Wang, C., Kajantie, E., Keikkala, E., Mustaniemi, S., Ronkainen, J., Sebert, S., Silva, W., Vääräsmäki, M., Jaddoe, V.W.V., Bernstein, R.M., Prentice, A.M., Cosin-Tomas, M., Dwyer, T., Håberg, S.E., Herceg, Z., Magnus, M.C., Munthe-Kaas, M.C., Page, C.M., Völker, M., Gilles, M., Send, T., Witt, S., Zillich, L., Gagliardi, L., Richiardi, L., Czamara, D., Räikkönen, K., Chatzi, L., Vafeiadi, M., Arshad, S.H., Ewart, S, Plusquin, M., Felix, J.F., Moore, S.E., Vrijheid, M., Holloway, J.W., Karmaus, W., Herberth, Gunda, Zenclussen, Ana Claudia, Streit, F., Lahti, J., Hüls, A., Hoang, T.T., London, S.J., Wiemels, J.L., Li, S., Spitz, N., Ghantous, A., Abrishamcar, S., Reimann, B., Marques, I., Silver, M.J., Aguilar-Lacasaña, S., Kitaba, N., Rezwan, F.I., Röder, Stefan, Sirignano, L., Tuhkanen, J., Mancano, G., Sharp, G.C., Metayer, C., Morimoto, L., Stein, D.J., Zar, H.J., Alfano, R., Nawrot, T., Wang, C., Kajantie, E., Keikkala, E., Mustaniemi, S., Ronkainen, J., Sebert, S., Silva, W., Vääräsmäki, M., Jaddoe, V.W.V., Bernstein, R.M., Prentice, A.M., Cosin-Tomas, M., Dwyer, T., Håberg, S.E., Herceg, Z., Magnus, M.C., Munthe-Kaas, M.C., Page, C.M., Völker, M., Gilles, M., Send, T., Witt, S., Zillich, L., Gagliardi, L., Richiardi, L., Czamara, D., Räikkönen, K., Chatzi, L., Vafeiadi, M., Arshad, S.H., Ewart, S, Plusquin, M., Felix, J.F., Moore, S.E., Vrijheid, M., Holloway, J.W., Karmaus, W., Herberth, Gunda, Zenclussen, Ana Claudia, Streit, F., Lahti, J., Hüls, A., Hoang, T.T., London, S.J., and Wiemels, J.L.
Abstract: Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.
Published: 2024

4. Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Author: Kadalayil, L., Alam, M., White, C.H., Ghantous, A., Walton, E., Gruzieva, O., Merid, S.K., Kumar, A., Roy, R., Solomon, O., Huen, K., Eskenazi, B., Rzehak, P., Grote, V., Langhendries, J.-P., Verduci, E., Ferre, N., Gruszfeld, D., Gao, L., Guan, W., Zeng, X., Schisterman, E.F., Dou, J., Bakulski, K.M., Feinberg, J.I., Soomro, M.H., Pesce, G., Baiz, N., Isaevska, E., Plusquin, M., Vafeiadi, M., Roumeliotaki, T., Langie, S.A.S., Standaert, A., Allard, C., Perron, P., Bouchard, L., van Meel, E.R., Felix, J.F., Jaddoe, V.W.V., Yousefi, P.D., Ramlau‑Hansen, C.H., Relton, C.L., Tobi, E.W., Starling, A.P., Yang, I.V., Llambrich, M., Santorelli, G., Lepeule, J., Salas, L.A., Bustamante, M., Ewart, S.L., Zhang, H., Karmaus, W., Röder, Stefan, Zenclussen, Ana Claudia, Jin, J., Nystad, W., Page, C.M., Magnus, M., Jima, D.D., Hoyo, C., Maguire, R.L., Kvist, T., Czamara, D., Räikkönen, K., Gong, T., Ullemar, V., Rifas‐Shiman, S.L., Oken, E., Almqvist, C., Karlsson, R., Lahti, J., Murphy, S.K., Håberg, S.E., London, S., Herberth, Gunda, Arshad, H., Sunyer, J., Grazuleviciene, R., Dabelea, D., Steegers‑Theunissen, R.P.M., Nohr, E.A., Sørensen, T.I.A., Duijts, L., Hivert, M.-F., Nelen, V., Popovic, M., Kogevinas, M., Nawrot, T.S., Herceg, Z., Annesi-Maesano, I., Fallin, M.D., Yeung, E., Breton, C.V., Koletzko, B., Holland, N., Melén, E., Sharp, G.C., Silver, M.J., Kadalayil, L., Alam, M., White, C.H., Ghantous, A., Walton, E., Gruzieva, O., Merid, S.K., Kumar, A., Roy, R., Solomon, O., Huen, K., Eskenazi, B., Rzehak, P., Grote, V., Langhendries, J.-P., Verduci, E., Ferre, N., Gruszfeld, D., Gao, L., Guan, W., Zeng, X., Schisterman, E.F., Dou, J., Bakulski, K.M., Feinberg, J.I., Soomro, M.H., Pesce, G., Baiz, N., Isaevska, E., Plusquin, M., Vafeiadi, M., Roumeliotaki, T., Langie, S.A.S., Standaert, A., Allard, C., Perron, P., Bouchard, L., van Meel, E.R., Felix, J.F., Jaddoe, V.W.V., Yousefi, P.D., Ramlau‑Hansen, C.H., Relton, C.L., Tobi, E.W., Starling, A.P., Yang, I.V., Llambrich, M., Santorelli, G., Lepeule, J., Salas, L.A., Bustamante, M., Ewart, S.L., Zhang, H., Karmaus, W., Röder, Stefan, Zenclussen, Ana Claudia, Jin, J., Nystad, W., Page, C.M., Magnus, M., Jima, D.D., Hoyo, C., Maguire, R.L., Kvist, T., Czamara, D., Räikkönen, K., Gong, T., Ullemar, V., Rifas‐Shiman, S.L., Oken, E., Almqvist, C., Karlsson, R., Lahti, J., Murphy, S.K., Håberg, S.E., London, S., Herberth, Gunda, Arshad, H., Sunyer, J., Grazuleviciene, R., Dabelea, D., Steegers‑Theunissen, R.P.M., Nohr, E.A., Sørensen, T.I.A., Duijts, L., Hivert, M.-F., Nelen, V., Popovic, M., Kogevinas, M., Nawrot, T.S., Herceg, Z., Annesi-Maesano, I., Fallin, M.D., Yeung, E., Breton, C.V., Koletzko, B., Holland, N., Melén, E., Sharp, G.C., and Silver, M.J.
Abstract: BackgroundSeasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.MethodsWe carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1–11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.ResultsWe identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).ConclusiosIn this large epigenome-wide meta-analysis study, we provide eviden
Published: 2023

5. Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude

Author: Universitat Rovira i Virgili, Kadalayil, L; Alam, MZ; White, CH; Ghantous, A; Walton, E; Gruzieva, O; Merid, SK; Kumar, A; Roy, RP; Solomon, O; Huen, K; Eskenazi, B; Rzehak, P; Grote, V; Langhendries, JP; Verduci, E; Ferre, N; Gruszfeld, D; Gao, L; Guan, WH; Zeng, XH; Schisterman, EF; Dou, JF; Bakulski, KM; Feinberg, JI; Soomro, MH; Pesce, G; Baiz, N; Isaevska, E; Plusquin, M; Vafeiadi, M; Roumeliotaki, T; Langie, SAS; Standaert, A; Allard, C; Perron, P; Bouchard, L; van Meel, ER; Felix, JF; Jaddoe, VWV; Yousefi, PD; Ramlau-Hansen, CH; Relton, CL; Tobi, EW; Starling, AP; Yang, IV; Llambrich, M; Santorelli, G; Lepeule, J; Salas, LA; Bustamante, M; Ewart, SL; Zhang, HM; Karmaus, W; Röder, S; Zenclussen, AC; Jin, JP; Nystad, W; Page, CM; Magnus, M; Jima, DD; Hoyo, C; Maguire, RL; Kvist, T; Czamara, D; Räikkönen, K; Gong, T; Ullemar, V; Rifas-Shiman, SL; Oken, E; Almqvist, C; Karlsson, R; Lahti, J; Murphy, SK; Håberg, SE; London, S; Herberth, G; Arshad, H; Sunyer, J; Grazuleviciene, R; Dabelea, D; Steegers-Theunissen, RPM; Nohr, EA; Sorensen, TIA; Duijts, L; Hivert, MF; Nelen, V; Popovic, M; Kogevinas, M; Nawrot, TS; Herceg, Z; Annesi-Maesano, I; Fallin, MD; Yeung, EDA; Breton, CV; Koletzko, B; Holland, N; Wiemels, JL; Melén, E; Sharp, GC; Silver, MJ; Rezwan, F; Holloway, JW, Universitat Rovira i Virgili, and Kadalayil, L; Alam, MZ; White, CH; Ghantous, A; Walton, E; Gruzieva, O; Merid, SK; Kumar, A; Roy, RP; Solomon, O; Huen, K; Eskenazi, B; Rzehak, P; Grote, V; Langhendries, JP; Verduci, E; Ferre, N; Gruszfeld, D; Gao, L; Guan, WH; Zeng, XH; Schisterman, EF; Dou, JF; Bakulski, KM; Feinberg, JI; Soomro, MH; Pesce, G; Baiz, N; Isaevska, E; Plusquin, M; Vafeiadi, M; Roumeliotaki, T; Langie, SAS; Standaert, A; Allard, C; Perron, P; Bouchard, L; van Meel, ER; Felix, JF; Jaddoe, VWV; Yousefi, PD; Ramlau-Hansen, CH; Relton, CL; Tobi, EW; Starling, AP; Yang, IV; Llambrich, M; Santorelli, G; Lepeule, J; Salas, LA; Bustamante, M; Ewart, SL; Zhang, HM; Karmaus, W; Röder, S; Zenclussen, AC; Jin, JP; Nystad, W; Page, CM; Magnus, M; Jima, DD; Hoyo, C; Maguire, RL; Kvist, T; Czamara, D; Räikkönen, K; Gong, T; Ullemar, V; Rifas-Shiman, SL; Oken, E; Almqvist, C; Karlsson, R; Lahti, J; Murphy, SK; Håberg, SE; London, S; Herberth, G; Arshad, H; Sunyer, J; Grazuleviciene, R; Dabelea, D; Steegers-Theunissen, RPM; Nohr, EA; Sorensen, TIA; Duijts, L; Hivert, MF; Nelen, V; Popovic, M; Kogevinas, M; Nawrot, TS; Herceg, Z; Annesi-Maesano, I; Fallin, MD; Yeung, EDA; Breton, CV; Koletzko, B; Holland, N; Wiemels, JL; Melén, E; Sharp, GC; Silver, MJ; Rezwan, F; Holloway, JW
Abstract: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation inclu
Published: 2023

6. Exposure to bushfire smoke is associated with clinical significant decrease in lung function in asthmatic children during the 2019/2020 Australian bushfire

Author: Da Silva Sena, C R, primary, Lines, O, additional, Latheef, M S, additional, Amarasinghe, G G, additional, Quah, W H, additional, Beyene, T, additional, Van Buskirk, J, additional, Hanigan, I, additional, Morgan, G, additional, Oldmeadow, C, additional, Platt, L, additional, Pearce, K, additional, Murphy, V, additional, Gibson, P G, additional, Karmaus, W, additional, Collison, A, additional, Dewaal, K, additional, and Mattes, J, additional
Published: 2022
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7. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

Author: Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, Holland, N, Solomon, O, Huen, K, Yousefi, P, Küpers, LK, González, JR, Suderman, M, Reese, SE, Page, CM, Gruzieva, O, Rzehak, P, Gao, L, Bakulski, KM, Novoloaca, A, Allard, C, Pappa, I, Llambrich, M, Vives, M, Jima, DD, Kvist, T, Baccarelli, A, White, C, Rezwan, FI, Sharp, GC, Tindula, G, Bergström, A, Grote, V, Dou, JF, Isaevska, E, Magnus, MC, Corpeleijn, E, Perron, P, Jaddoe, VWV, Nohr, EA, Maitre, L, Foraster, M, Hoyo, C, Håberg, SE, Lahti, J, DeMeo, DL, Zhang, H, Karmaus, W, Kull, I, Koletzko, B, Feinberg, JI, Gagliardi, L, Bouchard, L, Ramlau-Hansen, CH, Tiemeier, H, Santorelli, G, Maguire, RL, Czamara, D, Litonjua, AA, Langhendries, J-P, Plusquin, M, Lepeule, J, Binder, EB, Verduci, E, Dwyer, T, Carracedo, Á, Ferre, N, Eskenazi, B, Kogevinas, M, Nawrot, TS, Munthe-Kaas, MC, Herceg, Z, Relton, C, Melén, E, Gruszfeld, D, Breton, C, Fallin, MD, Ghantous, A, Nystad, W, Heude, B, Snieder, H, Hivert, M-F, Felix, JF, Sørensen, TIA, Bustamante, M, Murphy, SK, Raikkönen, K, Oken, E, Holloway, JW, Arshad, SH, London, SJ, and Holland, N
Abstract: BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.
Published: 2022

8. Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation

Author: Universitat Rovira i Virgili, Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N, Universitat Rovira i Virgili, and Solomon, O; Huen, K; Yousefi, P; Küpers, LK; González, JR; Suderman, M; Reese, SE; Page, CM; Gruzieva, O; Rzehak, P; Gao, L; Bakulski, KM; Novoloaca, A; Allard, C; Pappa, I; Llambrich, M; Vives, M; Jima, DD; Kvist, T; Baccarelli, A; White, C; Rezwan, FI; Sharp, GC; Tindula, G; Bergström, A; Grote, V; Dou, JF; Isaevska, E; Magnus, MC; Corpeleijn, E; Perron, P; Jaddoe, VWV; Nohr, EA; Maitre, L; Foraster, M; Hoyo, C; Håberg, SE; Lahti, J; DeMeo, DL; Zhang, HM; Karmaus, W; Kull, I; Koletzko, B; Feinberg, JI; Gagliardi, L; Bouchard, L; Ramlau-Hansen, CH; Tiemeier, H; Santorelli, G; Maguire, RL; Czamara, D; Litonjua, AA; Langhendries, JP; Plusquin, M; Lepeule, J; Binder, EB; Verduci, E; Dwyer, T; Carracedo, A; Ferre, N; Eskenazi, B; Kogevinas, M; Nawrot, TS; Munthe-Kaas, MC; Herceg, Z; Relton, C; Melén, E; Gruszfeld, D; Breton, C; Fallin, MD; Ghantous, A; Nystad, W; Heude, B; Snieder, H; Hivert, MF; Felix, JF; Sorensen, TIA; Bustamante, M; Murphy, SK; Raikkönen, K; Oken, E; Holloway, JW; Arshad, SH; London, SJ; Holland, N
Abstract: Background: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. Methods: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5–10 years from 8 cohorts (n = 4268). Results: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10−7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10−6) in older children and had methylation differences in the same direction. Conclusions: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.
Published: 2022

9. Infant feeding patterns and eczema in children in the first 6 years of life

Author: Soto‐Ramírez, N., Kar, S., Zhang, H., and Karmaus, W.
Published: 2017
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10. Expression of the filaggrin gene in umbilical cord blood predicts eczema risk in infancy: A birth cohort study

Author: Ziyab, A. H., Ewart, S., Lockett, G. A., Zhang, H., Arshad, H., Holloway, J. W., and Karmaus, W.
Published: 2017
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11. Maternal Levels of Dichlorodiphenyl-Dichloroethylene (DDE) May Increase Weight and Body Mass Index in Adult Female Offspring

Author: Karmaus, W., Osuch, J. R., Eneli, I., Mudd, L. M., Zhang, J., Mikucki, D., Haan, P., and Davis, S.
Published: 2009
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12. Auswertung epidemiologischer Untersuchungen zum Maurerberuf unter Kausalitätsgesichtspunkten

Author: Rehder, U., Karmaus, W., Wolter, Dietmar, editor, and Seide, Klaus, editor
Published: 1995
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13. Evaluating the efficacy of breastfeeding guidelines on long-term outcomes for allergic disease

Author: Bion, V., Lockett, G. A., Soto-Ramírez, N., Zhang, H., Venter, C., Karmaus, W., Holloway, J. W., and Arshad, S. H.
Published: 2016
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14. Twin Frequency and Industrial Pollution in Different Regions of Hesse, Germany

Author: Obi-Osius, N., Misselwitz, B., Karmaus, W., and Witten, J.
Published: 2004
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15. Sozialgruppenspezifische Einflüsse auf die Verschlechterung bronchialer Hyperreagibilitätssymptomatik bei Schulkindern

Author: Hendel-Kramer, A., Karmaus, W., Weiß, K., Moseler, M., Kühr, J., Forster, J., Laaser, Ulrich, editor, and Schwartz, Friedrich Wilhelm, editor
Published: 1992
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16. Does a Higher Number of Siblings Protect against the Development of Allergy and Asthma? A Review

Author: Karmaus, W. and Botezan, C.
Published: 2002

17. Cord blood group 2 innate lymphoid cells are associated with lung function at 6 weeks of age

Author: Martins Costa Gomes, G, de Gouveia Belinelo, P, Starkey, MR, Murphy, VE, Hansbro, PM, Sly, PD, Robinson, PD, Karmaus, W, Gibson, PG, Mattes, J, and Collison, AM
Subjects: 1107 Immunology, 1115 Pharmacology and Pharmaceutical Sciences
Abstract: Objective: Offspring born to mothers with asthma in pregnancy are known to have lower lung function which tracks with age. Human group 2 innate lymphoid cells (ILC2) accumulate in foetal lungs, at 10-fold higher levels compared to adult lungs. However, there are no data on foetal ILC2 numbers and the association with respiratory health outcomes such as lung function in early life. We aimed to investigate cord blood immune cell populations from babies born to mothers with asthma in pregnancy. Methods: Cord blood from babies born to asthmatic mothers was collected, and cells were stained in whole cord blood. Analyses were done using traditional gating approaches and computational methodologies (t-distributed stochastic neighbour embedding and PhenoGraph algorithms). At 6 weeks of age, the time to peak tidal expiratory flow as a percentage of total expiratory flow time (tPTEF/tE%) was determined as well as Lung Clearance Index (LCI), during quiet natural sleep. Results: Of 110 eligible infants (March 2017 to November 2019), 91 were successfully immunophenotyped (82.7%). Lung function was attempted in 61 infants (67.0%), and 43 of those infants (70.5% of attempted) had technically acceptable tPTEF/tE% measurements. Thirty-four infants (55.7% of attempted) had acceptable LCI measurements. Foetal ILC2 numbers with increased expression of chemoattractant receptor-homologous molecule (CRTh2), characterised by two distinct analysis methodologies, were associated with poorer infant lung function at 6 weeks of age." Conclusion: Foetal immune responses may be a surrogate variable for or directly influence lung function outcomes in early life.
Published: 2021

18. Exposure to stress and air pollution from bushfires during pregnancy: Could epigenetic changes explain effects on the offspring?

Author: Murphy, VE, Karmaus, W, Mattes, J, Brew, BK, Collison, A, Holliday, E, Jensen, ME, Morgan, GG, Zosky, GR, McDonald, VM, Jegasothy, E, Robinson, PD, Gibson, PG, Murphy, VE, Karmaus, W, Mattes, J, Brew, BK, Collison, A, Holliday, E, Jensen, ME, Morgan, GG, Zosky, GR, McDonald, VM, Jegasothy, E, Robinson, PD, and Gibson, PG
Abstract: Due to climate change, bushfires are becoming a more frequent and more severe phenomenon which contributes to poor health effects associated with air pollution. In pregnancy, environmental exposures can have lifelong consequences for the fetus, but little is known about these consequences in the context of bushfire smoke exposure. In this review we summarise the current knowledge in this area, and propose a potential mechanism linking bushfire smoke exposure in utero to poor perinatal and respiratory outcomes in the offspring. Bushfire smoke exposure is associated with poor pregnancy outcomes including reduced birth weight and an increased risk of prematurity. Some publications have outlined the adverse health effects on young children, particularly in relation to emergency department presentations and hospital admissions for respiratory problems, but there are no studies in children who were exposed to bushfire smoke in utero. Prenatal stress is likely to occur as a result of catastrophic bushfire events, and stress is known to be associated with poor perinatal and respiratory outcomes. Changes to DNA methylation are potential epigenetic mechanisms linking both smoke particulate exposure and prenatal stress to poor childhood respiratory health outcomes. More research is needed in large pregnancy cohorts exposed to bushfire events to explore this further, and to design appropriate mitigation interventions, in this area of global public health importance.
Published: 2021

19. Allergic sensitization and filaggrin variants predispose to the comorbidity of eczema, asthma, and rhinitis: results from the Isle of Wight birth cohort

Author: Ziyab, A. H., Karmaus, W., Zhang, H., Holloway, J. W., Steck, S. E., Ewart, S., and Arshad, S. H.
Published: 2014
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20. The diversity of young adult wheeze: a cluster analysis in a longitudinal birth cohort

Author: Kurukulaaratchy, R. J., Zhang, H., Raza, A., Patil, V., Karmaus, W., Ewart, S., and Arshad, S. H.
Published: 2014
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21. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Author: Vehmeijer, F.O.L. (Florianne O.L.), Küpers, A.M. (Marlijn), Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Lent, S. (Samantha), Jima, D.D. (Dereje D.), Tindula, G. (Gwen), Reese, S.E. (Sarah E.), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F.I. (Faisal I.), Melton, P.E. (Philip E.), Nohr, C. (Christian), Escaramís, G. (Geòrgia), 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), Bergström, A. (Anna), Binder, E.B. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (B.), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Håberg, S.E. (Siri E), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, C.A. (Christian), Langhendries, J.P. (Jean Paul), Lepeule, J. (Johanna), Magnus, M.C. (Maria C.), Maguire, R.L. (Rachel L.), Molloy, P.L. (Peter L.), Poppelaars-Monnereau, C. (Claire), Mori, T.A. (Trevor A.), Oken, E. (Emily), Räikkönen, K. (Katri), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J.M. (Judith), 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. (Carrie), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sørensen, T.I.A. (Thorkild), Huang, R.-C. (Rae-Chi), Arshad, S.H. (Syed), Nystad, W. (Wenche), Melén, E. (Erik), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S.K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A.A. (Andrea), Relton, C.L. (Caroline), Snieder, H. (Harold), Jaddoe, V.W.V. (Vincent), Felix, J.F. (Janine), Vehmeijer, F.O.L. (Florianne O.L.), Küpers, A.M. (Marlijn), Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Lent, S. (Samantha), Jima, D.D. (Dereje D.), Tindula, G. (Gwen), Reese, S.E. (Sarah E.), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F.I. (Faisal I.), Melton, P.E. (Philip E.), Nohr, C. (Christian), Escaramís, G. (Geòrgia), 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), Bergström, A. (Anna), Binder, E.B. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (B.), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Håberg, S.E. (Siri E), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, C.A. (Christian), Langhendries, J.P. (Jean Paul), Lepeule, J. (Johanna), Magnus, M.C. (Maria C.), Maguire, R.L. (Rachel L.), Molloy, P.L. (Peter L.), Poppelaars-Monnereau, C. (Claire), Mori, T.A. (Trevor A.), Oken, E. (Emily), Räikkönen, K. (Katri), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J.M. (Judith), 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. (Carrie), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sørensen, T.I.A. (Thorkild), Huang, R.-C. (Rae-Chi), Arshad, S.H. (Syed), Nystad, W. (Wenche), Melén, E. (Erik), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S.K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A.A. (Andrea), Relton, C.L. (Caroline), Snieder, H. (Harold), Jaddoe, V.W.V. (Vincent), and Felix, J.F. (Janine)
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 adolescent BMI.
Published: 2020
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22. 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.), Küpers, A.M. (Marlijn), 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.L. (Florianne O.L.), 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), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), 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), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, 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), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Melén, E. (Erik), Merid, S.K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G.C. (Gemma C.), Küpers, A.M. (Marlijn), 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.L. (Florianne O.L.), 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), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), 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), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, 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), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), and Melén, 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
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23. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author: Merid, SK, Novoloaca, A, Sharp, GC, Kupers, LK, Kho, AT, Roy, R, Gao, L, Annesi-Maesano, I, Jain, P, Plusquin, M, Kogevinas, M, Allard, C, Vehmeijer, FO, Kazmi, N, Salas, LA, Rezwan, FI, Zhang, H, Sebert, S, Czamara, D, Rifas-Shiman, SL, Melton, PE, Lawlor, DA, Pershagen, G, Breton, CV, Huen, K, Baiz, N, Gagliardi, L, Nawrot, TS, Corpeleijn, E, Perron, P, Duijts, L, Nohr, EA, Bustamante, M, Ewart, SL, Karmaus, W, Zhao, S, Page, CM, Herceg, Z, Jarvelin, M-R, Lahti, J, Baccarelli, AA, Anderson, D, Kachroo, P, Relton, CL, Bergstrom, A, Eskenazi, B, Soomro, MH, Vineis, P, Snieder, H, Bouchard, L, Jaddoe, VW, Sorensen, TIA, Vrijheid, M, Arshad, SH, Holloway, JW, Haberg, SE, Magnus, P, Dwyer, T, Binder, EB, DeMeo, DL, Vonk, JM, Newnham, J, Tantisira, KG, Kull, I, Wiemels, JL, Heude, B, Sunyer, J, Nystad, W, Munthe-Kaas, MC, Raikkonen, K, Oken, E, Huang, R-C, Weiss, ST, Anto, JM, Bousquet, J, Kumar, A, Soderhall, C, Almqvist, C, Cardenas, A, Gruzieva, O, Xu, C-J, Reese, SE, Kere, J, Brodin, P, Solomon, O, Wielscher, M, Holland, N, Ghantous, A, Hivert, M-F, Felix, JF, Koppelman, GH, London, SJ, Melen, E, Merid, SK, Novoloaca, A, Sharp, GC, Kupers, LK, Kho, AT, Roy, R, Gao, L, Annesi-Maesano, I, Jain, P, Plusquin, M, Kogevinas, M, Allard, C, Vehmeijer, FO, Kazmi, N, Salas, LA, Rezwan, FI, Zhang, H, Sebert, S, Czamara, D, Rifas-Shiman, SL, Melton, PE, Lawlor, DA, Pershagen, G, Breton, CV, Huen, K, Baiz, N, Gagliardi, L, Nawrot, TS, Corpeleijn, E, Perron, P, Duijts, L, Nohr, EA, Bustamante, M, Ewart, SL, Karmaus, W, Zhao, S, Page, CM, Herceg, Z, Jarvelin, M-R, Lahti, J, Baccarelli, AA, Anderson, D, Kachroo, P, Relton, CL, Bergstrom, A, Eskenazi, B, Soomro, MH, Vineis, P, Snieder, H, Bouchard, L, Jaddoe, VW, Sorensen, TIA, Vrijheid, M, Arshad, SH, Holloway, JW, Haberg, SE, Magnus, P, Dwyer, T, Binder, EB, DeMeo, DL, Vonk, JM, Newnham, J, Tantisira, KG, Kull, I, Wiemels, JL, Heude, B, Sunyer, J, Nystad, W, Munthe-Kaas, MC, Raikkonen, K, Oken, E, Huang, R-C, Weiss, ST, Anto, JM, Bousquet, J, Kumar, A, Soderhall, C, Almqvist, C, Cardenas, A, Gruzieva, O, Xu, C-J, Reese, SE, Kere, J, Brodin, P, Solomon, O, Wielscher, M, Holland, N, Ghantous, A, Hivert, M-F, Felix, JF, Koppelman, GH, London, SJ, and Melen, E
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

24. 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

25. 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

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

Author: Vehmeijer, Florianne, Küpers, LK, Sharp, GC, Salas, LA, Lent, S, Jima, DD, Tindula, G, Reese, S, Qi, C, Gruzieva, O, Page, C, Rezwan, FI, Melton, PE, Nohr, E, Escaramís, G, Rzehak, P, Heiskala, A, Gong, T, Tuominen, ST, Gao, L, Ross, JP, Starling, AP, Holloway, JW, Yousefi, P, Aasvang, GM, Beilin, LJ, Bergström, A, Binder, E, Chatzi, L, Corpeleijn, E, Czamara, D, Eskenazi, B, Ewart, S, Ferre, N, Grote, V, Gruszfeld, D, Håberg, SE, Hoyo, C, Huen, K, Karlsson, R, Kull, I, Langhendries, J P, Lepeule, J, Magnus, MC, Maguire, RL, Molloy, PL, Monnereau, Claire, Mori, TA, Oken, E, Räikkönen, K, Rifas-Shiman, S, Ruiz-Arenas, C, Sebert, S, Ullemar, V, Verduci, E, Vonk, JM, Xu, CJ, Yang, IV, Zhang, H, Zhang, W, Karmaus, W, Dabelea, D, Muhlhausler, BS, Breton, CV, Lahti, J, Almqvist, C, Jarvelin, M R R, Koletzko, B, Vrijheid, M, Sørensen, TIA, Huang, RC, Arshad, SH, Nystad, W, Melén, E, Koppelman, GH, London, SJ, Holland, N, Bustamante, M, Murphy, SK, Hivert, MF, Baccarelli, A, Relton, CL, Snieder, H, Jaddoe, Vincent, Felix, Janine, Vehmeijer, Florianne, Küpers, LK, Sharp, GC, Salas, LA, Lent, S, Jima, DD, Tindula, G, Reese, S, Qi, C, Gruzieva, O, Page, C, Rezwan, FI, Melton, PE, Nohr, E, Escaramís, G, Rzehak, P, Heiskala, A, Gong, T, Tuominen, ST, Gao, L, Ross, JP, Starling, AP, Holloway, JW, Yousefi, P, Aasvang, GM, Beilin, LJ, Bergström, A, Binder, E, Chatzi, L, Corpeleijn, E, Czamara, D, Eskenazi, B, Ewart, S, Ferre, N, Grote, V, Gruszfeld, D, Håberg, SE, Hoyo, C, Huen, K, Karlsson, R, Kull, I, Langhendries, J P, Lepeule, J, Magnus, MC, Maguire, RL, Molloy, PL, Monnereau, Claire, Mori, TA, Oken, E, Räikkönen, K, Rifas-Shiman, S, Ruiz-Arenas, C, Sebert, S, Ullemar, V, Verduci, E, Vonk, JM, Xu, CJ, Yang, IV, Zhang, H, Zhang, W, Karmaus, W, Dabelea, D, Muhlhausler, BS, Breton, CV, Lahti, J, Almqvist, C, Jarvelin, M R R, Koletzko, B, Vrijheid, M, Sørensen, TIA, Huang, RC, Arshad, SH, Nystad, W, Melén, E, Koppelman, GH, London, SJ, Holland, N, Bustamante, M, Murphy, SK, Hivert, MF, Baccarelli, A, Relton, CL, Snieder, H, Jaddoe, Vincent, and Felix, Janine
Published: 2020

27. DNA methylation of the filaggrin gene adds to the risk of eczema associated with loss-of-function variants

Author: Ziyab, A. H., Karmaus, W., Holloway, J. W., Zhang, H, Ewart, S., and Arshad, S. H.
Published: 2013
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28. Trends in cutaneous sensitization in the first 18 years of life: results from the 1989 Isle of Wight birth cohort study

Author: Roberts, G., Zhang, H., Karmaus, W., Raza, A., Scott, M., Matthews, S., Kurukulaaratchy, R. J., Dean, T., and Arshad, S. H.
Published: 2012
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29. The influence of gender and atopy on the natural history of rhinitis in the first 18 years of life

Author: Kurukulaaratchy, R. J., Karmaus, W., Raza, A., Matthews, S., Roberts, G., and Arshad, S. H.
Published: 2011
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30. Breast Milk Cytokines and Maternal Allergy: 488

Author: Burch, J. L., Soto-Ramirez, N., and Karmaus, W.
Published: 2011

31. The Association of Age of Puberty Onset and Adulthood Lung Function Is Mediated by Height Growth Rate in Adolescence

Author: Li, L., primary, Zhang, H., additional, Hasan Arshad, S., additional, John Henderson, A., additional, Relton, C.L., additional, Holloway, J.W., additional, Karmaus, W., additional, and Ewart, S., additional
Published: 2020
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32. DNA Methylation at Birth Is Associated with Asthma Acquisition from Pre- to Post- Adolescence Mediated by Atopy

Author: Rathod, A., primary, Zhang, H., additional, Arshad, S.H., additional, Ewart, S.L., additional, Karmaus, W., additional, and Holloway, J., additional
Published: 2020
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33. Association of BMI Trajectory in Earlier Childhood with Lung Function in Adulthood Is Mediated by DNA Methylation

Author: Patel, R., primary, Zhang, H., additional, Karmaus, W., additional, Ewart, S.L., additional, Arshad, S.H., additional, and Holloway, J., additional
Published: 2020
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34. The Association of Asthma Acquisition with DNA Methylation Changes During Adolescence Is Gender-Specific, A Genome-Wide Epigenetic Study

Author: Patel, R., primary, Solatikia, F., additional, Zhang, H., additional, Wolde, A., additional, Karmaus, W., additional, Ewart, S.L., additional, Relton, C., additional, Ring, S., additional, Henderson, J., additional, Arshad, S.H., additional, and Holloway, J., additional
Published: 2020
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35. Trends in eczema in the first 18 years of life: results from the Isle of Wight 1989 birth cohort study

Author: Ziyab, A. H., Raza, A., Karmaus, W., Tongue, N., Zhang, H., Matthews, S., Arshad, S. H., and Roberts, G.
Published: 2010
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36. Developments in the field of allergy in 2009 through the eyes of Clinical and Experimental Allergy

Author: Chu, H. W., Lloyd, C. M., Karmaus, W., Maestrelli, P., Mason, P., Salcedo, G., Thaikoottathil, J., and Wardlaw, A. J.
Published: 2010
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37. Trends in atopy in the first 18 years of life: results from the Isle of Wight birth cohort study: 100

Author: Roberts, G, Zhang, H, Karmaus, W, Raza, A, Scott, M, Matthews, S, Kurukulaaratchy, R, and Arshad, S
Published: 2010

38. Mütterliches Alter und Anzahl der Geschwister Kombinierte Wirkung familiärer Risikofaktoren auf die allergische Sensibilisierung: Kombinierte Wirkung familiärer Risikofaktoren auf die allergische Sensibilisierung

Author: Storm van’s Gravesande, K., Karmaus, W., Moseler, M., and Kühr, J.
Published: 1998
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39. Effect of breastfeeding duration on lung function at age 10 years: a prospective birth cohort study

Author: Ogbuanu, I U, Karmaus, W, Arshad, S H, Kurukulaaratchy, R J, and Ewart, S
Published: 2009
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40. Polymorphisms in the interleukin 13 and GATA binding protein 3 genes and the development of eczema during childhood

Author: Arshad, S. H., Karmaus, W., Kurukulaaratchy, R., Sadeghnejad, A., Huebner, M., and Ewart, S.
Published: 2008

41. Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns:Findings From the Pregnancy and Childhood Epigenetics Consortium

Author: Kazmi, N, Sharp, GC, Reese, SE, Vehmeijer, FO, Lahti, J, Page, CM, Zhang, WM, Rifas-Shiman, SL, Rezwan, FI, Simpkin, AJ, Burrows, K, Richardson, TG, Ferreira, D L S, Fraser, A, Harmon, QE, Zhao, SS, Jaddoe, Vincent, Czamara, D, Binder, EB, Magnus, MC, Haberg, SE, Nystad, W, Nohr, EA, Starling, AP, Kechris, KJ, Yang, IV, DeMeo, DL, Litonjua, AA, Baccarelli, A, Oken, E, Holloway, JW, Karmaus, W, Arshad, SH, Dabelea, D, Sorensen, TIA, Laivuori, H, Raikkonen, K, Felix, Janine, London, SJ, Hivert, MF, Gaunt, TR, Lawlor, DA, Relton, CL, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Developmental Psychology Research Group, Helsinki Collegium for Advanced Studies, University of Helsinki, HUS Gynecology and Obstetrics, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland, Pregnancy and Genes, University Management, Department of Medical and Clinical Genetics, Helsinki Institute of Life Science HiLIFE, Faculty of Medicine, Epidemiology, Erasmus MC other, and Pediatrics
Subjects: Adult, pre-eclampsia, hypertension, BIRTH, HYPOMETHYLATION, VASOPRESSIN, BLOOD-PRESSURE, Gestational Age, Epigenesis, Genetic, preeclampsia, Cohort Studies, Hypertension, Pregnancy-Induced/diagnosis, Pregnancy, gestational hypertension, Humans, COHORT, gestational age, METAANALYSIS, ASSOCIATIONS, DNA methylation, epigenetics, NORWEGIAN MOTHER, Infant, Newborn, Pregnancy Outcome, DNA, ALSPAC, Fetal Blood, cardiovascular diseases, 3121 General medicine, internal medicine and other clinical medicine, GENERATION R, FETAL-GROWTH, Female, methylation, DNA-Binding Proteins/genetics, Infant, Premature, Genome-Wide Association Study, DNA Methylation/genetics
Abstract: Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R-2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.
Published: 2019

42. 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

43. Airway Hyperresponsiveness and Body Mass Index: The Child Health and Environment Cohort Study in Hesse, Germany

Author: Eneli, I. U., Karmaus, W. K., Davis, S., and Kuehr, J.
Published: 2006
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44. Clinical markers in adult offspring of families with and without Balkan Endemic Nephropathy

Author: Dimitrov, P, Tsolova, S, Georgieva, R, Bozhilova, D, Simeonov, V, Bonev, A, and Karmaus, W
Published: 2006

45. Risk factors for childhood asthma and recurrent wheezy bronchitis

Author: Frischer, T., Kuehr, J., Meinert, R., Karmaus, W., and Urbanek, R.
Published: 1993
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46. Does allo-immune reactivity play a role in the prenatal programming of childhood allergy?

Author: Karmaus, W. and Gangur, V.
Published: 2005

47. 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

48. Hypertensive Disorders of Pregnancy and DNA Methylation in Newborns Findings From the Pregnancy and Childhood Epigenetics Consortium

Author: Kazmi, N., Sharp, G.C. (Gregory), Reese, SE, Vehmeijer, F.O., Lahti, J. (Jari), Page, CM, Zhang, W.M., Rifas-Shiman, S.L. (Sheryl L.), Rezwan, F.I., Simpkin, A.J., Burrows, K., Richardson, T.G., Ferreira, D. L. S., Fraser, A, Harmon, Q.E., Zhao, S.S., Jaddoe, V.W.V. (Vincent), Czamara, D. (Darina), Binder, E.B. (Elisabeth), Magnus, M.C., Håberg, S.E. (Siri E), Nystad, W. (Wenche), Nohr, C. (Christian), Starling, A.P., Kechris, K.J., Yang, I.V., Demeo, D.L. (Dawn), Litonjua, AA, Baccarelli, A., Oken, E. (Emily), Holloway, J.W. (John), Karmaus, W, Arshad, S.H. (Syed), Dabelea, D., Sorensen, H.G., Laivuori, H, Raikkonen, K. (Katri), Felix, J.F. (Janine), London, S.J. (Stephanie), Hivert, M.-F. (Marie-France), Gaunt, T.R. (Tom), Lawlor, D.A. (Debbie), Relton, C.L. (Caroline), Kazmi, N., Sharp, G.C. (Gregory), Reese, SE, Vehmeijer, F.O., Lahti, J. (Jari), Page, CM, Zhang, W.M., Rifas-Shiman, S.L. (Sheryl L.), Rezwan, F.I., Simpkin, A.J., Burrows, K., Richardson, T.G., Ferreira, D. L. S., Fraser, A, Harmon, Q.E., Zhao, S.S., Jaddoe, V.W.V. (Vincent), Czamara, D. (Darina), Binder, E.B. (Elisabeth), Magnus, M.C., Håberg, S.E. (Siri E), Nystad, W. (Wenche), Nohr, C. (Christian), Starling, A.P., Kechris, K.J., Yang, I.V., Demeo, D.L. (Dawn), Litonjua, AA, Baccarelli, A., Oken, E. (Emily), Holloway, J.W. (John), Karmaus, W, Arshad, S.H. (Syed), Dabelea, D., Sorensen, H.G., Laivuori, H, Raikkonen, K. (Katri), Felix, J.F. (Janine), London, S.J. (Stephanie), Hivert, M.-F. (Marie-France), Gaunt, T.R. (Tom), Lawlor, D.A. (Debbie), and Relton, C.L. (Caroline)
Abstract: Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.
Published: 2019
Full Text: View/download PDF

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

Author: Küpers, LK, Monnereau, C, Sharp, GC, Yousefi, P, Salas, LA, Ghantous, A, Page, CM, Reese, SE, Wilcox, AJ, Czamara, D, Starling, AP, Novoloaca, A, Lent, S, Roy, R, Hoyo, C, Breton, CV, Allard, C, Just, AC, Bakulski, KM, Holloway, JW, Everson, TM, Xu, C-J, Huang, R-C, van der Plaat, DA, Wielscher, M, Merid, SK, Ullemar, V, Rezwan, FI, Lahti, J, van Dongen, J, Langie, SAS, Richardson, TG, Magnus, MC, Nohr, EA, Xu, Z, Duijts, L, Zhao, S, Zhang, W, Plusquin, M, DeMeo, DL, Solomon, O, Heimovaara, JH, Jima, DD, Gao, L, Bustamante, M, Perron, P, Wright, RO, Hertz-Picciotto, I, Zhang, H, Karagas, MR, Gehring, U, Marsit, CJ, Beilin, LJ, Vonk, JM, Jarvelin, M-R, Bergström, A, Örtqvist, AK, Ewart, S, Villa, PM, Moore, SE, Willemsen, G, Standaert, ARL, Håberg, SE, Sørensen, TIA, Taylor, JA, Räikkönen, K, Yang, IV, Kechris, K, Nawrot, TS, Silver, MJ, Gong, YY, Richiardi, L, Kogevinas, M, Litonjua, AA, Eskenazi, B, Huen, K, Mbarek, H, Maguire, RL, Dwyer, T, Vrijheid, M, Bouchard, L, Baccarelli, AA, Croen, LA, Karmaus, W, Anderson, D, de Vries, M, Sebert, S, Kere, J, Karlsson, R, Arshad, SH, Hämäläinen, E, Routledge, MN, Boomsma, DI, Feinberg, AP, Newschaffer, CJ, Govarts, E, Moisse, M, Fallin, MD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, M-F, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Davey Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H, Felix, JF, Küpers, LK, Monnereau, C, Sharp, GC, Yousefi, P, Salas, LA, Ghantous, A, Page, CM, Reese, SE, Wilcox, AJ, Czamara, D, Starling, AP, Novoloaca, A, Lent, S, Roy, R, Hoyo, C, Breton, CV, Allard, C, Just, AC, Bakulski, KM, Holloway, JW, Everson, TM, Xu, C-J, Huang, R-C, van der Plaat, DA, Wielscher, M, Merid, SK, Ullemar, V, Rezwan, FI, Lahti, J, van Dongen, J, Langie, SAS, Richardson, TG, Magnus, MC, Nohr, EA, Xu, Z, Duijts, L, Zhao, S, Zhang, W, Plusquin, M, DeMeo, DL, Solomon, O, Heimovaara, JH, Jima, DD, Gao, L, Bustamante, M, Perron, P, Wright, RO, Hertz-Picciotto, I, Zhang, H, Karagas, MR, Gehring, U, Marsit, CJ, Beilin, LJ, Vonk, JM, Jarvelin, M-R, Bergström, A, Örtqvist, AK, Ewart, S, Villa, PM, Moore, SE, Willemsen, G, Standaert, ARL, Håberg, SE, Sørensen, TIA, Taylor, JA, Räikkönen, K, Yang, IV, Kechris, K, Nawrot, TS, Silver, MJ, Gong, YY, Richiardi, L, Kogevinas, M, Litonjua, AA, Eskenazi, B, Huen, K, Mbarek, H, Maguire, RL, Dwyer, T, Vrijheid, M, Bouchard, L, Baccarelli, AA, Croen, LA, Karmaus, W, Anderson, D, de Vries, M, Sebert, S, Kere, J, Karlsson, R, Arshad, SH, Hämäläinen, E, Routledge, MN, Boomsma, DI, Feinberg, AP, Newschaffer, CJ, Govarts, E, Moisse, M, Fallin, MD, Melén, E, Prentice, AM, Kajantie, E, Almqvist, C, Oken, E, Dabelea, D, Boezen, HM, Melton, PE, Wright, RJ, Koppelman, GH, Trevisi, L, Hivert, M-F, Sunyer, J, Munthe-Kaas, MC, Murphy, SK, Corpeleijn, E, Wiemels, J, Holland, N, Herceg, Z, Binder, EB, Davey Smith, G, Jaddoe, VWV, Lie, RT, Nystad, W, London, SJ, Lawlor, DA, Relton, CL, Snieder, H, and Felix, JF
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

50. 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

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