Methylation and Autism

twinsThis article in Molecular Psychiatry is impressive in scope, details, and importance (see link below).

This is the first systemic epigenomic analyses of monozygotic (MZ) twins (genetically identical) who are discordant (one has and one doesn’t have) for autism.  It shows the role of altered DNA methylation in autism. 

I’m reminded of the magnitude of the importance of the JAMA Feb 13th 2013 article on prenatal folate and autism rates in Norway, which showed an autism rate of 1 in 500 in moms who did not take folate and 1 in 1000 in moms who did.  Folate and vitamin B-12 are the key to the methylation cycle that provides the all important methyl groups needed for the methylation that is discussed in this article.

Even though there is a high genetic predisposition for autism (last year published at 23% chance of having a subsequent autism child if you have one), the cause is not a direct hard-wired genetic one as in down syndrome (trisomy 21).  This study, due to the considerable variability in symptoms of these concordant MZ twins, shows the cause is epigenetic, meaning it is environmental, how the environment affects methylation of the genes.  This is very important for parents to understand, because if the methylation can be repaired, there can be recovery, and there certainly can be significant reductions in future risks to other unborn children.

Epigenetic, meaning reversible changes of gene expression, independent of your DNA sequence, has been associated with brain development, drug addiction, autism spectrum, and other neuropsychiatric disorders, including psychosis, Rett syndrome, and Fragile-X. Epigenetic mechanisms have also been implicated for type 1 diabetes which doesn’t surprise me one bit.  

The hard core scientists among you will need to read the entire study design.  

Results of this study show that Autism Spectrum Disorders are not associated with global differences in DNA methylation but rather specific DMR gene regions.  Some of these were previously noted in the literature including: GABRB3AFF2NLGN2,JMJD1CSNRPNSNURFUBE3A and KCNJ10.

The top-ranked DMR located in the promoter region of PIK3C3 (cg19837131) was significantly hypomethylated in affected individuals compared with their unaffected co-twins”

“Given the known gender difference in DNA methylation across the X chromosome, these analyses were restricted to probes on the autosomes (N=22 678) to minimize gender-induced biases.”

 

The results of this impressive study show:

“1. Supports the association of variable DNA methylation with phenotypic differences between genetically identical individuals

2.  The observed DNA methylation differences in MZ twins discordant for ASD and ASD-related traits, who are otherwise matched for genotype, shared environment, age, sex, and other potential confounders, highlight the role of non-shared environmental and stochastic factors in the etiology of autism. These findings concur with mounting data suggesting that environmentally mediated effects on the epigenome may be relatively common and important for disease.

3.  Although DNA methylation at some CpG sites is consistently altered across the entire set of discordant twins, differences at other CpG sites are specific to certain symptom groups… significant genetic heterogeneity between the three core symptoms of ASD

4.  Considerable familial heterogeneity, with rare epigenetic alterations of large magnitude being potentially associated with ASD

5.  Significant correlations between DNA methylation and autism symptom scores across our sample cohort suggest that there is a quantitative relationship between the severity of the autistic phenotype and epigenetic variation at certain loci. This reinforces the view of autism as the quantitative extreme of a phenotypic spectrum and highlights the potential use of epigenetic biomarkers as a predictor for severity of symptoms

6.  in addition to implicating a number of novel genes in the etiology of ASD, we identified ASD-associated differential DNA methylation in the vicinity of multiple loci previously implicated in the pathogenesis of autism in genetic studies, including AFF2AUTS2GABRB3NLGN3NRXN1SLC6A4 andUBE3A (see Supplementary Table 12 for a comprehensive list)”

Take home message: avoid toxins that could harm your methylation cycle (heavy metals, pesticides, plastics) and take your Vitamin B-12, folate, and D.  Vitamin C and E will help in keeping you toxin free. Best way to stay toxin free is an organic diet heavy on fruits and vegetables prepared at home. Keep your GI track in tip top shape as it’s the main barrier to toxins that would otherwise disrupt your methylation.  If you are already struggling with GI issues, consider comprehensive digestive stool analysis, food sensitivity testing, and then either the GAPS diet or targeted interventions based on the findings of those tests. If you have any health challenges, particularly that involve brain function in any way, it would be best to assume you have gut issues.

Read the Study Here

Dr. Paul

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