Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy

Eva Morales, Nadia Vilahur, Lucas A. Salas, Valeria Motta, Mariana F. Fernandez, Mario Murcia, Sabrina Llop, Adonina Tardon, Guillermo Fernandez-Tardon, Loreto Santa-Marina, Mara Gallastegui, Valentina Bollati, Xavier P. Estivill, Nicolas Olea, Jordi Sunyer, Mariona Bustamante

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1644-1655
Number of pages12
JournalInternational Journal of Epidemiology
Volume45
Issue number5
Publication statusPublished - 1 Oct 2016

Fingerprint

DNA Methylation
Placenta
Methylation
Smoking
Mothers
Genome
Pregnancy
Mendelian Randomization Analysis
Cotinine
Genome-Wide Association Study
Random Allocation
Urine
Parturition
Genes

Keywords

  • birthweight
  • DNA methylation
  • epigenetics
  • fetal programming
  • placenta
  • tobacco smoking

ASJC Scopus subject areas

  • Epidemiology

Cite this

Morales, E., Vilahur, N., Salas, L. A., Motta, V., Fernandez, M. F., Murcia, M., ... Bustamante, M. (2016). Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy. International Journal of Epidemiology, 45(5), 1644-1655.

Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy. / Morales, Eva; Vilahur, Nadia; Salas, Lucas A.; Motta, Valeria; Fernandez, Mariana F.; Murcia, Mario; Llop, Sabrina; Tardon, Adonina; Fernandez-Tardon, Guillermo; Santa-Marina, Loreto; Gallastegui, Mara; Bollati, Valentina; Estivill, Xavier P.; Olea, Nicolas; Sunyer, Jordi; Bustamante, Mariona.

In: International Journal of Epidemiology, Vol. 45, No. 5, 01.10.2016, p. 1644-1655.

Research output: Contribution to journalArticle

Morales, E, Vilahur, N, Salas, LA, Motta, V, Fernandez, MF, Murcia, M, Llop, S, Tardon, A, Fernandez-Tardon, G, Santa-Marina, L, Gallastegui, M, Bollati, V, Estivill, XP, Olea, N, Sunyer, J & Bustamante, M 2016, 'Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy', International Journal of Epidemiology, vol. 45, no. 5, pp. 1644-1655.
Morales, Eva ; Vilahur, Nadia ; Salas, Lucas A. ; Motta, Valeria ; Fernandez, Mariana F. ; Murcia, Mario ; Llop, Sabrina ; Tardon, Adonina ; Fernandez-Tardon, Guillermo ; Santa-Marina, Loreto ; Gallastegui, Mara ; Bollati, Valentina ; Estivill, Xavier P. ; Olea, Nicolas ; Sunyer, Jordi ; Bustamante, Mariona. / Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy. In: International Journal of Epidemiology. 2016 ; Vol. 45, No. 5. pp. 1644-1655.
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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.",
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AU - Morales, Eva

AU - Vilahur, Nadia

AU - Salas, Lucas A.

AU - Motta, Valeria

AU - Fernandez, Mariana F.

AU - Murcia, Mario

AU - Llop, Sabrina

AU - Tardon, Adonina

AU - Fernandez-Tardon, Guillermo

AU - Santa-Marina, Loreto

AU - Gallastegui, Mara

AU - Bollati, Valentina

AU - Estivill, Xavier P.

AU - Olea, Nicolas

AU - Sunyer, Jordi

AU - Bustamante, Mariona

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N2 - 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.

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KW - epigenetics

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