Eva Morales1,2, Nadia Vilahur2,3,4,5, Lucas A Salas2,3,5,6, Valeria Motta7, Mariana F Fernandez2,8, Mario Murcia2,9, Sabrina Llop2,9, Adonina Tardon2,10, Guillermo Fernandez-Tardon2,10, Loreto Santa-Marina2,11,12, Mara Gallastegui12,13, Valentina Bollati7, Xavier Estivill2,4,5, Nicolas Olea2,8, Jordi Sunyer2,3,5, Mariona Bustamante2,3,4,5. 1. IMIB-Arrixaca Biomedical Research Institute, Virgen de la Arrixaca University Hospital, 30120 Murcia, Spain, embarto@hotmail.com. 2. CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain. 3. Centre for Research in Environmental Epidemiology (CREAL), 08003 Barcelona, Catalonia, Spain. 4. Genomics and Disease Group, Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, 08003 Barcelona, Catalonia, Spain. 5. Universitat Pompeu Fabra (UPF), 08003 Barcelona, Catalonia, Spain. 6. Department of Epidemiology, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA. 7. EPIGET-Epidemiology, Epigenetics and Toxicology Lab-Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milano, Italy. 8. Instituto de Investigación Biosanitaria (ibs.GRANADA), University of Granada, San Cecilio University Hospital, 18012 Granada, Spain. 9. FISABIO-Universitat de València-Universitat Jaume I Joint Research Unit of Epidemiology and Environmental Health, 46020 Valencia, Spain. 10. Molecular Epidemiology of Cancer Unit, University Institute of Oncology, University of Oviedo, 33003 Oviedo, Spain. 11. Subdirección de Salud Pública y Adicciones de Gipuzkoa, 20010 Donostia/San Sebastián, Spain. 12. Instituto de Investigación Sanitaria BIODONOSTIA, 20014 Donostia/San Sebastián, Spain and. 13. Faculty of Pharmacy, University of the Basque Country UPV/EHU, 01006 Vitoria-Gasteiz, Spain.
Abstract
BACKGROUND: We conducted an epigenome-wide association study (EWAS) of DNA methylation in placenta in relation to maternal tobacco smoking during pregnancy and examined whether smoking-induced changes lead to low birthweight. METHODS: DNA methylation in placenta was measured using the Illumina HumanMethylation450 BeadChip in 179 participants from the INfancia y Medio Ambiente (INMA) birth cohort. Methylation levels across 431 311 CpGs were tested for differential methylation between smokers and non-smokers in pregnancy. We took forward three top-ranking loci for further validation and replication by bisulfite pyrosequencing using data of 248 additional participants of the INMA cohort. We examined the association of methylation at smoking-associated loci with birthweight by applying a mediation analysis and a two-sample Mendelian randomization approach. RESULTS: Fifty CpGs were differentially methylated in placenta between smokers and non-smokers during pregnancy [false discovery rate (FDR) < 0.05]. We validated and replicated differential methylation at three top-ranking loci: cg27402634 located between LINC00086 and LEKR1, a gene previously related to birthweight in genome-wide association studies; cg20340720 (WBP1L); and cg25585967 and cg12294026 (TRIO). Dose-response relationships with maternal urine cotinine concentration during pregnancy were confirmed. Differential methylation at cg27402634 explained up to 36% of the lower birthweight in the offspring of smokers (Sobel P-value < 0.05). A two-sample Mendelian randomization analysis provided evidence that decreases in methylation levels at cg27402634 lead to decreases in birthweight. CONCLUSIONS: We identified novel loci differentially methylated in placenta in relation to maternal smoking during pregnancy. Adverse effects of maternal smoking on birthweight of the offspring may be mediated by alterations in the placental methylome.
BACKGROUND: We conducted an epigenome-wide association study (EWAS) of DNA methylation in placenta in relation to maternal tobacco smoking during pregnancy and examined whether smoking-induced changes lead to low birthweight. METHODS: DNA methylation in placenta was measured using the Illumina HumanMethylation450 BeadChip in 179 participants from the INfancia y Medio Ambiente (INMA) birth cohort. Methylation levels across 431 311 CpGs were tested for differential methylation between smokers and non-smokers in pregnancy. We took forward three top-ranking loci for further validation and replication by bisulfite pyrosequencing using data of 248 additional participants of the INMA cohort. We examined the association of methylation at smoking-associated loci with birthweight by applying a mediation analysis and a two-sample Mendelian randomization approach. RESULTS: Fifty CpGs were differentially methylated in placenta between smokers and non-smokers during pregnancy [false discovery rate (FDR) < 0.05]. We validated and replicated differential methylation at three top-ranking loci: cg27402634 located between LINC00086 and LEKR1, a gene previously related to birthweight in genome-wide association studies; cg20340720 (WBP1L); and cg25585967 and cg12294026 (TRIO). Dose-response relationships with maternal urine cotinine concentration during pregnancy were confirmed. Differential methylation at cg27402634 explained up to 36% of the lower birthweight in the offspring of smokers (Sobel P-value < 0.05). A two-sample Mendelian randomization analysis provided evidence that decreases in methylation levels at cg27402634 lead to decreases in birthweight. CONCLUSIONS: We identified novel loci differentially methylated in placenta in relation to maternal smoking during pregnancy. Adverse effects of maternal smoking on birthweight of the offspring may be mediated by alterations in the placental methylome.
Authors: Linda Valeri; Sarah L Reese; Shanshan Zhao; Christian M Page; Wenche Nystad; Brent A Coull; Stephanie J London Journal: Epigenomics Date: 2017-02-21 Impact factor: 4.778
Authors: Andres Cardenas; Sharon M Lutz; Todd M Everson; Patrice Perron; Luigi Bouchard; Marie-France Hivert Journal: Am J Epidemiol Date: 2019-11-01 Impact factor: 4.897
Authors: Lucas A Salas; Lauren C Peres; Zaneta M Thayer; Rick Wa Smith; Yichen Guo; Wonil Chung; Jiahui Si; Liming Liang Journal: Epigenomics Date: 2021-03-10 Impact factor: 4.778