Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Autism
Published in: Molecular Autism 1/2016

Open Access 01-12-2016 | Research

Placental methylome analysis from a prospective autism study

Authors: Diane I. Schroeder, Rebecca J. Schmidt, Florence K. Crary-Dooley, Cheryl K. Walker, Sally Ozonoff, Daniel J. Tancredi, Irva Hertz-Picciotto, Janine M. LaSalle

Published in: Molecular Autism | Issue 1/2016

Login to get access

Abstract

Background

Autism spectrum disorders (ASD) are increasingly prevalent neurodevelopmental disorders that are behaviorally diagnosed in early childhood. Most ASD cases likely arise from a complex mixture of genetic and environmental factors, an interface where the epigenetic marks of DNA methylation may be useful as risk biomarkers. The placenta is a potentially useful surrogate tissue characterized by a methylation pattern of partially methylated domains (PMDs) and highly methylated domains (HMDs) reflective of methylation patterns observed in the early embryo.

Methods

In this study, we investigated human term placentas from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) prospective study by whole genome bisulfite sequencing. We also examined the utility of PMD/HMDs in detecting methylation differences consistent with ASD diagnosis at age three.

Results

We found that while human placental methylomes have highly reproducible PMD and HMD locations, there is a greater variation between individuals in methylation levels over PMDs than HMDs due to both sampling and individual variability. In a comparison of methylation differences in placental samples from 24 ASD and 23 typically developing (TD) children, a HMD containing a putative fetal brain enhancer near DLL1 was found to reach genome-wide significance and was validated for significantly higher methylation in ASD by pyrosequencing.

Conclusions

These results suggest that the placenta could be an informative surrogate tissue for predictive ASD biomarkers in high-risk families.
Appendix
Available only for authorised users
Literature
1.
Center for Disease Control and Prevention. Prevalence and characteristics of autism spectrum disorder among children aged 8 years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. MMWR Surveill Summ. 2016;65:1-23.
2.
Messinger D, Young GS, Ozonoff S, Dobkins K, Carter A, Zwaigenbaum L, Landa RJ, Charman T, Stone WL, Constantino JN, et al. Beyond autism: a baby siblings research consortium study of high-risk children at three years of age. J Am Acad Child Adolesc Psychiatry. 2013;52(3):300–8. e301.CrossRefPubMedPubMedCentral
3.
Chawarska K, Shic F, Macari S, Campbell DJ, Brian J, Landa R, Hutman T, Nelson CA, Ozonoff S, Tager-Flusberg H, et al. 18-month predictors of later outcomes in younger siblings of children with autism spectrum disorder: a baby siblings research consortium study. J Am Acad Child Adolesc Psychiatry. 2014;53(12):1317–27. e1311.CrossRefPubMedPubMedCentral
4.
Ozonoff S, Young GS, Carter A, Messinger D, Yirmiya N, Zwaigenbaum L, Bryson S, Carver LJ, Constantino JN, Dobkins K, et al. Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics. 2011;128(3):e488–95.PubMedPubMedCentral
5.
Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci. 2015;16(9):551–63.CrossRefPubMed
6.
7.
8.
Hellerstedt WL, McGovern PM, Fontaine P, Oberg CN, Cordes JE. Prenatal environmental exposures and child health: Minnesota’s role in the National Children's Study. Minn Med. 2008;91(9):40–3.PubMed
9.
10.
Roberts AL, Lyall K, Hart JE, Laden F, Just AC, Bobb JF, Koenen KC, Ascherio A, Weisskopf MG. Perinatal air pollutant exposures and autism spectrum disorder in the children of nurses’ health study II participants. Environ Health Perspect. 2013;121(8):978–84.PubMedPubMedCentral
11.
Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tassone F, Hertz-Picciotto I. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am J Clin Nutr. 2012;96(1):80–9.CrossRefPubMedPubMedCentral
12.
13.
Estes A, Munson J, Rogers SJ, Greenson J, Winter J, Dawson G. Long-term outcomes of early intervention in 6-year-old children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2015;54(7):580–7.CrossRefPubMedPubMedCentral
14.
15.
Flanagan JM. Epigenome-wide association studies (EWAS): past, present, and future. Methods Mol Biol. 2015;1238:51–63.CrossRefPubMed
16.
Schroeder DI, Blair JD, Lott P, Yu HO, Hong D, Crary F, Ashwood P, Walker C, Korf I, Robinson WP, et al. The human placenta methylome. Proc Natl Acad Sci U S A. 2013;110(15):6037–42.CrossRefPubMedPubMedCentral
17.
Schroeder DI, Lott P, Korf I, LaSalle JM. Large-scale methylation domains mark a functional subset of neuronally expressed genes. Genome Res. 2011;21(10):1583–91.CrossRefPubMedPubMedCentral
18.
Schroeder DI, Jayashankar K, Douglas KC, Thirkill TL, York D, Dickinson PJ, Williams LE, Samollow PB, Ross PJ, Bannasch DL, et al. Early developmental and evolutionary origins of gene body DNA methylation patterns in mammalian placentas. PLoS Genet. 2015;11(8):e1005442.CrossRefPubMedPubMedCentral
19.
Walker CK, Anderson KW, Milano KM, Ye S, Tancredi DJ, Pessah IN, Hertz-Picciotto I, Kliman HJ. Trophoblast inclusions are significantly increased in the placentas of children in families at risk for autism. Biol Psychiatry. 2013;74(3):204–11.CrossRefPubMedPubMedCentral
20.
Lord C, Risi S, Lambrecht L, Cook Jr EH, Leventhal BL, DiLavore PC, Pickles A, Rutter M. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30(3):205–23.CrossRefPubMed
21.
Lord C, Rutter M, DiLavore PC, Risi S. The Autism Diagnostic Observation Schedule (ADOS). Los Angeles: Western Psychological Services; 2000.
22.
23.
24.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57(1):289–300.
25.
Bozdogan H. Model selection and Akaike’s Information Criterion (AIC): the general theory and its analytical extensions. Psychometrika. 1987;52(3):345–70.CrossRef
26.
Akaike H. Information theory and an extension of the maximum likelihood principle. In: Csaki BNPBF, editor. Second international symposium on information theory. Budapest: Academiai Kiado; 1973.
27.
Cotton AM, Avila L, Penaherrera MS, Affleck JG, Robinson WP, Brown CJ. Inactive X chromosome-specific reduction in placental DNA methylation. Hum Mol Genet. 2009;18(19):3544–52.CrossRefPubMedPubMedCentral
28.
Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30.CrossRefPubMedPubMedCentral
29.
Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, Sanborn AL, Machol I, Omer AD, Lander ES, et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159(7):1665–80.CrossRefPubMed
30.
Shimojo H, Ohtsuka T, Kageyama R. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron. 2008;58(1):52–64.CrossRefPubMed
31.
Shimojo H, Isomura A, Ohtsuka T, Kori H, Miyachi H, Kageyama R. Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis. Genes Dev. 2016;30(1):102–16.CrossRefPubMedPubMedCentral
32.
Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, Parada LF. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J Neurosci. 2012;32(17):5880–90.CrossRefPubMed
33.
Chen J, Alberts I, Li X. Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders. Int J Dev Neurosci. 2014;35:35–41.CrossRefPubMed
34.
Hormozdiari F, Penn O, Borenstein E, Eichler EE. The discovery of integrated gene networks for autism and related disorders. Genome Res. 2015;25(1):142–54.CrossRefPubMedPubMedCentral
35.
Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R. Why are autism spectrum conditions more prevalent in males? PLoS Biol. 2011;9(6):e1001081.CrossRefPubMedPubMedCentral
36.
Nugent BM, Wright CL, Shetty AC, Hodes GE, Lenz KM, Mahurkar A, Russo SJ, Devine SE, McCarthy MM. Brain feminization requires active repression of masculinization via DNA methylation. Nat Neurosci. 2015;18(5):690–7.CrossRefPubMedPubMedCentral
37.
Dhiman VK, Attwood K, Campbell MJ, Smiraglia DJ. Hormone stimulation of androgen receptor mediates dynamic changes in DNA methylation patterns at regulatory elements. Oncotarget. 2015;6(40):42575–89.PubMedPubMedCentral
38.
Otti GR, Saleh L, Velicky P, Fiala C, Pollheimer J, Knofler M. Notch2 controls prolactin and insulin-like growth factor binding protein-1 expression in decidualizing human stromal cells of early pregnancy. PLoS ONE. 2014;9(11):e112723.CrossRefPubMedPubMedCentral
39.
Murta D, Batista M, Trindade A, Silva E, Mateus L, Duarte A, Lopes-da-Costa L. Dynamics of Notch signalling in the mouse oviduct and uterus during the oestrous cycle. Reprod Fertil Dev. 2015;28(11):1663–78. doi:10.1071/RD15029.CrossRef
40.
Baron-Cohen S, Auyeung B, Norgaard-Pedersen B, Hougaard DM, Abdallah MW, Melgaard L, Cohen AS, Chakrabarti B, Ruta L, Lombardo MV. Elevated fetal steroidogenic activity in autism. Mol Psychiatry. 2015;20(3):369–76.CrossRefPubMed
41.
Huuskonen P, Amezaga MR, Bellingham M, Jones LH, Storvik M, Hakkinen M, Keski-Nisula L, Heinonen S, O'Shaughnessy PJ, Fowler PA, et al. The human placental proteome is affected by maternal smoking. Reprod Toxicol. 2016;63:22–31.CrossRefPubMedPubMedCentral
42.
Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP. Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry. 2014;19(8):862–71.CrossRefPubMed
43.
Nardone S, Sams DS, Reuveni E, Getselter D, Oron O, Karpuj M, Elliott E. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014;4:e433.CrossRefPubMedPubMedCentral
44.
Feinberg JI, Bakulski KM, Jaffe AE, Tryggvadottir R, Brown SC, Goldman LR, Croen LA, Hertz-Picciotto I, Newschaffer CJ, Fallin MD, et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. Int J Epidemiol. 2015;44(4):1199–210.CrossRefPubMedPubMedCentral
45.
Berko ER, Suzuki M, Beren F, Lemetre C, Alaimo CM, Calder RB, Ballaban-Gil K, Gounder B, Kampf K, Kirschen J, et al. Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder. PLoS Genet. 2014;10(5):e1004402.CrossRefPubMedPubMedCentral
46.
CV B, CJ M, E F, K N, JM G, DC D, J H, N H, JM L, R S et al: Small magnitude effect sizes in epigenetic endpoints are important in children’s environmental health studies. Environ Health Perspect. in press.
47.
Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009;7:62.CrossRefPubMedPubMedCentral
48.
Behnia F, Parets SE, Kechichian T, Yin H, Dutta EH, Saade GR, Smith AK, Menon R. Fetal DNA methylation of autism spectrum disorders (ASD) candidate genes: association with spontaneous preterm birth. Am J Obstet Gynecol. 2015;212(4):533.e1–9.CrossRef
49.
James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP. Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum. Transl Psychiatry. 2014;4:e460.CrossRefPubMedPubMedCentral
50.
James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP. Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Transl Psychiatry. 2013;3:e232.CrossRefPubMedPubMedCentral
51.
Nagarajan RP, Patzel KA, Martin M, Yasui DH, Swanberg SE, Hertz-Picciotto I, Hansen RL, Van de Water J, Pessah IN, Jiang R, et al. MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res. 2008;1(3):169–78.CrossRefPubMedPubMedCentral
52.
Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics. 2006;1(4):e1–11.CrossRefPubMedPubMedCentral
53.
Wang YS Z. Chapter 4, Cell Types of the Placenta. In: Vascular biology of the placenta. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.
54.
Van Handel B, Prashad SL, Hassanzadeh-Kiabi N, Huang A, Magnusson M, Atanassova B, Chen A, Hamalainen EI, Mikkola HK. The first trimester human placenta is a site for terminal maturation of primitive erythroid cells. Blood. 2010;116(17):3321–30.CrossRefPubMedPubMedCentral
55.
de Goede OM, Razzaghian HR, Price EM, Jones MJ, Kobor MS, Robinson WP, Lavoie PM. Nucleated red blood cells impact DNA methylation and expression analyses of cord blood hematopoietic cells. Clin Epigenetics. 2015;7:95.CrossRefPubMedPubMedCentral
56.
Bakulski KM, Feinberg JI, Andrews SV, Yang J, Brown S, Mckenney SL, Witter F, Walston J, Feinberg AP, Fallin MD. DNA methylation of cord blood cell types: applications for mixed cell birth studies. Epigenetics. 2016;11(5):354–62.CrossRefPubMed
Metadata
Title
Placental methylome analysis from a prospective autism study
Authors
Diane I. Schroeder
Rebecca J. Schmidt
Florence K. Crary-Dooley
Cheryl K. Walker
Sally Ozonoff
Daniel J. Tancredi
Irva Hertz-Picciotto
Janine M. LaSalle
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2016
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-016-0114-8

Other articles of this Issue 1/2016

Molecular Autism 1/2016 Go to the issue

Research

Olfactory processing in adults with autism spectrum disorders

Short report

Mimetic desire in autism spectrum disorder

Erratum

Erratum to: Sex differences in the association between infant markers and later autistic traits

Research

Altered functional connectivity of the amygdaloid input nuclei in adolescents and young adults with autism spectrum disorder: a resting state fMRI study

Erratum

Erratum to: Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits

Research

Basic and complex emotion recognition in children with autism: cross-cultural findings