DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth

Hwajin Lee, Andrew Jaffe, Jason I. Feinberg, Rakel Tryggvadottir, Shannon Brown, Carolina Montano, Martin J. Aryee, Rafael A. Irizarry, Julie Herbstman, Frank R Witter, Lynn R. Goldman, Andrew P Feinberg, Daniele Daniele Fallin

Research output: Contribution to journalArticle

Abstract

Background: Gestational age at birth strongly predicts neonatal, adolescent and adult morbidity and mortality through mostly unknown mechanisms. Identification of specific genes that are undergoing regulatory change prior to birth, such as through changes in DNA methylation, would increase our understanding of developmental changes occurring during the third trimester and consequences of pre-term birth (PTB). Methods: We performed a genome-wide analysis of DNA methylation (using microarrays, specifically CHARM 2.0) in 141 newborns collected in Baltimore, MD, using novel statistical methodology to identify genomic regions associated with gestational age at birth. Bisulphite pyrosequencing was used to validate significant differentially methylated regions (DMRs), and real-time PCR was performed to assess functional significance of differential methylation in a subset of newborns. Results: We identified three DMRs at genome-wide significance levels adjacent to the NFIX, RAPGEF2 and MSRB3 genes. All three regions were validated by pyrosequencing, and RAGPEF2 also showed an inverse correlation between DNA methylation levels and gene expression levels. Although the three DMRs appear very dynamic with gestational age in our newborn sample, adult DNA methylation levels at these regions are stable and of equal or greater magnitude than the oldest neonate, directionally consistent with the gestational age results. Conclusions: We have identified three differentially methylated regions associated with gestational age at birth. All three nearby genes play important roles in the development of several organs, including skeletal muscle, brain and haematopoietic system. Therefore, they may provide initial insight into the basis of PTB's negative health outcomes. The genome-wide custom DNA methylation array technology and novel statistical methods employed in this study could constitute a model for epidemiologic studies of epigenetic variation. Published by Oxford University Press on behalf of the International Epidemiological Association

Original languageEnglish (US)
Article numberdyr237
Pages (from-to)188-199
Number of pages12
JournalInternational Journal of Epidemiology
Volume41
Issue number1
DOIs
StatePublished - Feb 2012

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DNA Methylation
Gestational Age
Parturition
Genome
Newborn Infant
Term Birth
Hematopoietic System
Baltimore
Third Pregnancy Trimester
Regulator Genes
Oligonucleotide Array Sequence Analysis
Epigenomics
Methylation
Genes
Real-Time Polymerase Chain Reaction
Epidemiologic Studies
Skeletal Muscle
Technology
Morbidity
Gene Expression

Keywords

  • Differentially methylated regions
  • Epigenetic epidemiology
  • Genome-wide DNA methylation
  • Gestational age
  • Pre-term birth

ASJC Scopus subject areas

  • Epidemiology

Cite this

DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. / Lee, Hwajin; Jaffe, Andrew; Feinberg, Jason I.; Tryggvadottir, Rakel; Brown, Shannon; Montano, Carolina; Aryee, Martin J.; Irizarry, Rafael A.; Herbstman, Julie; Witter, Frank R; Goldman, Lynn R.; Feinberg, Andrew P; Fallin, Daniele Daniele.

In: International Journal of Epidemiology, Vol. 41, No. 1, dyr237, 02.2012, p. 188-199.

Research output: Contribution to journalArticle

Lee, H, Jaffe, A, Feinberg, JI, Tryggvadottir, R, Brown, S, Montano, C, Aryee, MJ, Irizarry, RA, Herbstman, J, Witter, FR, Goldman, LR, Feinberg, AP & Fallin, DD 2012, 'DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth', International Journal of Epidemiology, vol. 41, no. 1, dyr237, pp. 188-199. https://doi.org/10.1093/ije/dyr237
Lee, Hwajin ; Jaffe, Andrew ; Feinberg, Jason I. ; Tryggvadottir, Rakel ; Brown, Shannon ; Montano, Carolina ; Aryee, Martin J. ; Irizarry, Rafael A. ; Herbstman, Julie ; Witter, Frank R ; Goldman, Lynn R. ; Feinberg, Andrew P ; Fallin, Daniele Daniele. / DNA methylation shows genome-wide association of NFIX, RAPGEF2 and MSRB3 with gestational age at birth. In: International Journal of Epidemiology. 2012 ; Vol. 41, No. 1. pp. 188-199.
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AU - Jaffe, Andrew

AU - Feinberg, Jason I.

AU - Tryggvadottir, Rakel

AU - Brown, Shannon

AU - Montano, Carolina

AU - Aryee, Martin J.

AU - Irizarry, Rafael A.

AU - Herbstman, Julie

AU - Witter, Frank R

AU - Goldman, Lynn R.

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N2 - Background: Gestational age at birth strongly predicts neonatal, adolescent and adult morbidity and mortality through mostly unknown mechanisms. Identification of specific genes that are undergoing regulatory change prior to birth, such as through changes in DNA methylation, would increase our understanding of developmental changes occurring during the third trimester and consequences of pre-term birth (PTB). Methods: We performed a genome-wide analysis of DNA methylation (using microarrays, specifically CHARM 2.0) in 141 newborns collected in Baltimore, MD, using novel statistical methodology to identify genomic regions associated with gestational age at birth. Bisulphite pyrosequencing was used to validate significant differentially methylated regions (DMRs), and real-time PCR was performed to assess functional significance of differential methylation in a subset of newborns. Results: We identified three DMRs at genome-wide significance levels adjacent to the NFIX, RAPGEF2 and MSRB3 genes. All three regions were validated by pyrosequencing, and RAGPEF2 also showed an inverse correlation between DNA methylation levels and gene expression levels. Although the three DMRs appear very dynamic with gestational age in our newborn sample, adult DNA methylation levels at these regions are stable and of equal or greater magnitude than the oldest neonate, directionally consistent with the gestational age results. Conclusions: We have identified three differentially methylated regions associated with gestational age at birth. All three nearby genes play important roles in the development of several organs, including skeletal muscle, brain and haematopoietic system. Therefore, they may provide initial insight into the basis of PTB's negative health outcomes. The genome-wide custom DNA methylation array technology and novel statistical methods employed in this study could constitute a model for epidemiologic studies of epigenetic variation. Published by Oxford University Press on behalf of the International Epidemiological Association

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