The landscape of DNA methylation amid a perfect storm of autism aetiologies

Ciernia, Annie Vogel; LaSalle, Janine M.

doi:10.1038/nrn.2016.41

Cited by 141 publications

(109 citation statements)

References 137 publications

(152 reference statements)

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“…For two of these putative novel ASD-risk genes, mutations were found in at least three families from our data (Supplementary Figure 2); MED13, which is related to the intellectual disability gene MED13L 38 , carried putative damaging mutations in three families. PHF3 mutations, with PHF2 involved in ASD 24 , were found in four families; this gene encodes a PHD finger protein that regulates transcription by influencing chromatin structure 39 , a mechanism increasingly being implicated in ASD 17, 21, 40 . Some other mutation-intolerant genes were implicated in three or more families included PER2 and HECTD4 (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

et al. 2017

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We are performing whole genome sequencing (WGS) of families with Autism Spectrum Disorder (ASD) to build a resource, named MSSNG, to enable the sub-categorization of phenotypes and underlying genetic factors involved. Here, we report WGS of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible in a cloud platform, and through an internet portal with controlled access. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertion/deletions (indels) or copy number variations (CNVs) per ASD subject. We identified 18 new candidate ASD-risk genes such as MED13 and PHF3, and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (p=6×10−4). In 294/2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried CNV/chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

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Section: Resultsmentioning

confidence: 99%

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

et al. 2017

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“…Not only is fetal growth restriction strongly associated with developmental programming that has been attributed to DNA methylation 55,56 and histone acetylation, 57 ASD has also been associated with epigenetic changes. 58-60 Here, too, “double jeopardy” might come into play because epigenetic phenomena have also been associated with inflammation. 61-64 …”

Section: Discussionmentioning

confidence: 99%

Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks’ gestation

Joseph¹,

Korzeniewski²,

Allred³

et al. 2017

American Journal of Obstetrics and Gynecology

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BACKGROUND No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder (ASD), separately among those with and without cognitive impairment. OBJECTIVE To identify perinatal factors associated with increased risk for ASD with and without intellectual disability (ID: IQ < 70) in children born extremely preterm. STUDY DESIGN This prospective multi-center (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks gestation in 2002-2004 who were evaluated for ASD and ID at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal ‘infection’ refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4) or other/unspecified infection (n=43; e.g., chlamydia, trichomonas or herpes, etc.). We do not know the extent to which ‘infection’ per se was confirmed by microbial colonization. We use the terms ‘fetal growth restriction’ and ‘small for gestational age’ interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth-restriction was defined as a birth weight Z-score for gestational age at delivery < - 2 (i.e., 2 standard deviations or more below the median birth weight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into four groups based on whether or not they met rigorous diagnostic criteria for ASD and ID (ASD+/ID−, ASD+/ID+, ASD−/ID+ and ASD−/ID−). Temporally-ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for ASD and/or ID (ASD+/ID−, ASD+/ID+ and ASD−/ID+). RESULTS 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for ASD; of these, 840 (98%) children were assessed for ID. ASD+/ID− was diagnosed in 3.2% (27/840), ASD+/ID+ in 3.8% (32/840), and ASD−/ID+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal ‘infection’ during pregnancy was associated with increased risk of ASD+/ID+ (odd ratio [OR], 2.7; 95% CI, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of ASD+/ID+ (OR, 2.9; 95% CI, 1.3-6.6) and ASD+/ID− (OR, 4.4; 95% CI, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for ASD+/ID− (OR, 9.9; 95% CI, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of ASD−/ID+ (OR, 2.9; 95% CI, 1.2-6.7). CONCLUSION Our study confirms that low gestational age is associated with increased risk for ASD irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with ASD without ID. Maternal report of cervical-vaginal infection is associated with increased risk of ASD with ID, and per...

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“…Epigenetics is defined as modifications to nucleotides or chromatin that can modify phenotype without changing DNA sequence. Epigenetic marks such as DNA methylation (Lister et al, 2013) and histone modifications (Fagiolini et al, 2009) are at the interface of genetic and environmental interactions during the dynamic process of human brain development and are implicated in the etiology of ASD (Ladd-Acosta et al, 2014; Nardone et al, 2014; Vogel Ciernia and LaSalle, 2016). Interestingly, folate is a major dietary methyl donor for DNA and histone methylation reactions, and use of folic acid-containing prenatal vitamins at conception was protective for ASD, particularly in mothers with the MTHFR TT genotype (Schmidt et al, 2011; Schmidt et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes

et al. 2016

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Summary Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find significant global DNA hypomethylation that is enriched over autism candidate genes and impacts gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of >1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes.

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The landscape of DNA methylation amid a perfect storm of autism aetiologies

Cited by 141 publications

References 137 publications

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks’ gestation

Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes

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