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Epigenetics of Autism Spectrum Disorder

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Neuroepigenomics in Aging and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((PMISB,volume 978))

Abstract

Autism spectrum disorder (ASD), one of the most common childhood neurodevelopmental disorders (NDDs), is diagnosed in 1 of every 68 children. ASD is incredibly heterogeneous both clinically and aetiologically. The etiopathogenesis of ASD is known to be complex, including genetic, environmental and epigenetic factors. Normal epigenetic marks modifiable by both genetics and environmental exposures can result in epigenetic alterations that disrupt the regulation of gene expression, negatively impacting biological pathways important for brain development. In this chapter we aim to summarize some of the important literature that supports a role for epigenetics in the underlying molecular mechanism of ASD. We provide evidence from work in genetics, from environmental exposures and finally from more recent studies aimed at directly determining ASD-specific epigenetic patterns, focusing mainly on DNA methylation (DNAm). Finally, we briefly discuss some of the implications of current research on potential epigenetic targets for therapeutics and novel avenues for future work.

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Abbreviations

5-hmC:

5-Hydroxymethylcytosine

5-mC:

5-Methylcytosine

Δβ:

Difference in DNA methylation

ADHD:

Attention deficit and hyperactivity disorder

ARID1B:

AT-rich interaction domain 1B

ART:

Assisted reproductive technologies

AS:

Angelman syndrome

ASD:

Autism spectrum disorder

ATP:

Adenosine triphosphate

BA10:

Brodmann area 10

BA19:

Brodmann area 19

BA24:

Brodmann area 24

BBB:

Blood–brain barrier

BCL-2:

BCL2, apoptosis regulator

BPA:

Bisphenol A

BWS:

Beckwith-Wiedemann syndrome

C11orf21:

Chromosome 11 open reading frame 21

C1Q:

Complement subcomponent C1q

CBL:

Cerebellum

CDKL5:

Cyclin-dependent kinase-like 5

CHARGE:

Coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities and ear abnormalities/deafness

CHD7:

Chromodomain helicase DNA-binding protein 7

CHD8:

Chromodomain helicase DNA-binding protein 8

CNV:

Copy number variant

DGCR6:

DiGeorge critical region 6

DGCR8:

DiGeorge critical region 8

DLGAP1:

DLG associated protein 1

DLGAP2:

DLG associated protein 2

DNAm:

DNA methylation

DNMT:

DNA methyl transferases

FDR:

False discovery rate

FMR1:

Fragile X mental retardation 1

GAD65:

Glutamic acid decarboxylase 65

GDM:

Gestational diabetes mellitus

GOM:

Gain of methylation

GRIN2B:

Glutamate ionotropic receptor NMDA type subunit 2B

GxE:

Gene by environment interactions

H3K27ac:

Histone 3 lysine 27 acetylation

H3K4me3:

Histone 3 lysine 4 trimethylation

HDAC:

Histone deacetylase

HUWE1:

HECT, UBA and WWE domain-containing 1, E3 ubiquitin protein

IC:

Imprinting centre

ID:

Intellectual disability

KDM6A:

Lysine demethylase 6A

KMT2D:

Lysine methyltransferase 2D

lncRNA:

Long noncoding RNA

LOF:

Loss of function

LOM:

Loss of methylation

MBDs:

Methyl-CpG-binding proteins

MECP2:

Methyl-CpG-binding protein 2

miRNA:

Micro-RNA

MZ:

Monozygotic

NDD:

Neurodevelopmental disorder

NRXN1:

Neurexin 1

NSD1:

Nuclear receptor SET (su(var)3–9, enhancer-of-zeste, trithorax) domain-containing protein-1 gene

OCM:

One carbon metabolism

OR:

Odds ratio

OXTR:

Oxytocin receptor

PDD-NOS:

Pervasive developmental disorder – not otherwise specified

PFC:

Prefrontal cortex

PRRT1:

Proline-rich transmembrane protein 1

PTEN:

Phosphatase and tensin homolog

RELN:

Reelin

RORA:

Retinoic acid-related orphan receptor

RTT:

Rett syndrome

SAM:

S-Adenosyl methionine

SHANK3:

SH3 and multiple ankyrin repeat domains 3

SNP:

Single-nucleotide polymorphism

SNRPN:

Small nuclear ribonucleoprotein polypeptide N

TC:

Temporal cortex

TNF-α:

Tumour necrosis factor alpha

TSPAN32:

Tetraspanin 32

UBE3A:

Ubiquitin protein ligase

UBE3A:

Ubiquitin protein ligase E3A

UPD:

Uniparental disomy

VPA:

Valproic acid

VUS:

Variant of unknown significance

WGS:

Whole genome sequencing

ZFP57:

ZFP57 zinc finger protein

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  1. Program in Genetics and Genome Biology, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada

    Michelle T. Siu Ph.D. & Rosanna Weksberg M.D., Ph.D.

  2. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Ave, Toronto, ON, M5G 1X8, Canada

    Rosanna Weksberg M.D., Ph.D.

  3. Department of Paediatrics, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Rosanna Weksberg M.D., Ph.D.

  4. Institute of Medical Science, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Rosanna Weksberg M.D., Ph.D.

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  1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), CATALONIA, Spain

    Raul Delgado-Morales

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Siu, M.T., Weksberg, R. (2017). Epigenetics of Autism Spectrum Disorder. In: Delgado-Morales, R. (eds) Neuroepigenomics in Aging and Disease. Advances in Experimental Medicine and Biology(), vol 978. Springer, Cham. https://doi.org/10.1007/978-3-319-53889-1_4

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