DNA Methylation and Susceptibility to Autism Spectrum Disorder

Tremblay, Monique; Jiang, Yong‐Hui

doi:10.1146/annurev-med-120417-091431

Cited by 93 publications

(70 citation statements)

References 101 publications

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“…DNA methylation has long been implicated as a contributor to the etiology of ASD-related disorders, such as Rett syndrome and Fragile X [ 53 , 54 , 55 , 56 ]. With respect to idiopathic ASD, we were the first to demonstrate that DNA methylation differences across multiple genes could be correlated to dysregulated expression of those genes in LCLs from discordantly diagnosed monozygotic twins and sibling pairs [ 7 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Lee

2020

IJMS

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Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with core deficits in social communication and manifestation of restricted, repetitive, and stereotyped behaviors. Despite the core symptomatology, ASD is extremely heterogeneous with respect to the severity of symptoms and behaviors. This heterogeneity presents an inherent challenge to all large-scale genome-wide omics analyses. In the present study, we address this heterogeneity by stratifying ASD probands from simplex families according to the severity of behavioral scores on the Autism Diagnostic Interview-Revised diagnostic instrument, followed by re-analysis of existing DNA methylation data from individuals in three ASD subphenotypes in comparison to that of their respective unaffected siblings. We demonstrate that subphenotyping of cases enables the identification of over 1.6 times the number of statistically significant differentially methylated regions (DMR) and DMR-associated genes (DAGs) between cases and controls, compared to that identified when all cases are combined. Our analyses also reveal ASD-related neurological functions and comorbidities that are enriched among DAGs in each phenotypic subgroup but not in the combined case group. Moreover, relational gene networks constructed with the DAGs reveal signaling pathways associated with specific functions and comorbidities. In addition, a network comprised of DAGs shared among all ASD subgroups and the combined case group is enriched in genes involved in inflammatory responses, suggesting that neuroinflammation may be a common theme underlying core features of ASD. These findings demonstrate the value of phenotype definition in methylomic analyses of ASD and may aid in the development of subtype-directed diagnostics and therapeutics.

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Section: Resultsmentioning

confidence: 99%

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Lee

2020

IJMS

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“…DNA methylation is the most commonly studied epigenetic mark and occurs when a methyl group is added to the fifth carbon of cytosine in a cytosine-guanine dinucleotide (CpG) context in mammals. Differential methylation is highly relevant for neuropsychiatric diseases and has been identified in association with schizophrenia [ 37 – 42 ], depression [ 43 – 46 ], anxiety [ 47 – 50 ], and autism spectrum disorder [ 51 – 55 ]. Several studies have identified differential methylation patterns in the sperm of humans and rats directly exposed to THC, particularly at the autism candidate locus DLGAP2 , and a study by Watson et al demonstrated that parental THC shifts DNA methylation of genes relevant for glutamatergic signaling in the rat nucleus accumbens [ 56 – 58 ].…”

Section: Introductionmentioning

confidence: 99%

Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

et al. 2021

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Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

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“…In this context, epigenetic processes have emerged as a plausible mechanism by which environmental exposures can lead to long-lasting alterations, such as variation in brain structure or neuronal circuits, found in psychiatric disorders [5][6][7] . There is growing evidence that epigenetic dysregulation is a feature of ADHD 6,[8][9][10][11] , depression 12 , autism [13][14][15][16] , schizophrenia 17,18 and bipolar disorder 19 .…”

Section: Introductionmentioning

confidence: 99%

Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults

et al. 2020

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Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that often persists into adulthood. There is growing evidence that epigenetic dysregulation participates in ADHD. Given that only a limited number of epigenome-wide association studies (EWASs) of ADHD have been conducted so far and they have mainly focused on pediatric and population-based samples, we performed an EWAS in a clinical sample of adults with ADHD. We report one CpG site and four regions differentially methylated between patients and controls, which are located in or near genes previously involved in autoimmune diseases, cancer or neuroticism. Our sensitivity analyses indicate that smoking status is not responsible for these results and that polygenic risk burden for ADHD does not greatly impact the signatures identified. Additionally, we show an overlap of our EWAS findings with genetic signatures previously described for ADHD and with epigenetic signatures for smoking behavior and maternal smoking. These findings support a role of DNA methylation in ADHD and emphasize the need for additional efforts in larger samples to clarify the role of epigenetic mechanisms on ADHD across the lifespan.

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DNA Methylation and Susceptibility to Autism Spectrum Disorder

Cited by 93 publications

References 101 publications

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Phenotypic Subtyping and Re-Analysis of Existing Methylation Data from Autistic Probands in Simplex Families Reveal ASD Subtype-Associated Differentially Methylated Genes and Biological Functions

Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

Epigenome-wide association study of attention-deficit/hyperactivity disorder in adults

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