The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

Lahiri, Debomoy K.; Maloney, Bryan; Zawia, Nasser H.

doi:10.1038/mp.2009.82

Cited by 194 publications

(169 citation statements)

References 106 publications

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“…Genetic and/or environmentally-induced alterations in folate-dependent one carbon metabolism (transmethylation and epigenetics) linked to methioninedependent sulfur metabolism (transsulfuration and oxidative stress) offers another plausible framework that could connect some of these disparate functional correlates of autism. Epigenetic alterations and oxidative DNA damage observed in the present study are consistent with the geneenvironment model proposed in the LEARn (Latent Earlylife Associated Regulation) explanation for idiopathic neurobiologic diseases (Lahiri et al 2009). The LEARn model proposes that genetic and environmental risk factors operate through alterations in DNA methylation and oxidative damage in susceptible genes resulting in altered gene expression.…”

supporting

confidence: 78%

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

James¹

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY) 2012 REPORT TYPE Final DATES COVERED (From -To) TITLE AND SUBTITLE Redox Abnormalities as a Vulnerability Phenotype for Autism 5a. CONTRACT NUMBERand Related Alterations in CNS Development 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Sandra Jill James, Ph.D.5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERArkansas Children's Hospital Research Institute Little Rock, AR 72202 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, MD 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release; distribution unlimited SUPPLEMENTARY NOTES ABSTRACT:We hypothesize that low systemic redox potential (GSH/GSSG; cysteine/cystine) reflects a vulnerability phenotype that is associated with regressive autism and is predictive of the risk of developing autism. The redox vulnerability phenotype is associated with epigenetic alterations in primary immune cells that may be reversible with restoration of intracellular redox potential. The hypothesis predicts that children with regressive autism and high risk (developmentally-delayed) children who are subsequently diagnosed with autism will exhibit lower redox potential compared to age-matched unaffected control children. It also predicts that low redox potential from these children will be associated with epigenetic modifications in DNA methylation and histone acetylation/methylation that are reversible with treatment to restore redox potential. In Aim 1 we will determine whether redox potential in immune cells can be used as a biomarker for regressive autism and whether it is predictive of the subsequent diagnosis of autism. We will also evaluate immune redox potential from high risk developmentally delayed children to determine whether redox status is predictive of subsequent development of autism. In Aim 2, we will determine whether immune cells from autistic children are associated with altered cytokine patterns,...

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supporting

confidence: 78%

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

James¹

2012

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“…5), to account for the razor thin genetic load margin between clinically ill subjects and normal controls, which leaves a major role to be played by the environment [Lahiri et al, 2009;Niculescu et al, 2009]. A stressful/ hostile environment may lead to sub-threshold illness even in normal genetic load individuals, whereas a favorable environment may lead to supra normative functioning in certain life areas for individuals who carry a higher genetic risk.…”

Section: Discussionmentioning

confidence: 99%

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Patel

Le-Niculescu

Koller

et al. 2010

American J of Med Genetics Pt B

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We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.

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“…One of the most intriguing (but also complicating) characteristics of the dynamics of epigenetic changes is that they may have originated in the early life of the organi sm and become manifest in the elderly [ 67 ].…”

Section: Dna Methylation and Neurodegenerationmentioning

confidence: 99%

The ‘golden age’ of DNA methylation in neurodegenerative diseases

Fuso¹

2013

Clinical Chemistry and Laboratory Medicine

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DNA methylation reactions are regulated, in the first instance, by enzymes and the intermediates that constitute the ' so called ' one-carbon metabolism. This is a complex biochemical pathway, also known as the homocysteine cycle, regulated by the presence of B vitamins (folate, B6, B12) and choline, among other metabolites. One of the intermediates of this metabolism is S-adenosylmethionine, which represent the methyl donor in all the DNA methyltransferase reactions in eukaryotes. The one-carbon metabolism therefore produces the substrate necessary for the transferring of a methyl group on the cytosine residues of DNA; S-adenosylmethionine also regulates the activity of the enzymes that catalyze this reaction, namely the DNA methyltransferases (DNMTs). Alterations of this metabolic cycle can therefore be responsible for aberrant DNA methylation processes possibly leading to several human diseases. As a matter of fact, increasing evidences indicate that a number of human diseases with multifactorial origin may have an epigenetic basis. This is also due to the great technical advances in the field of epigenetic research. Among the human diseases associated with epigenetic factors, aging-related and neurodegenerative diseases are probably the object of most intense research. This review will present the main evidences linking seve ral human diseases to DNA methylation, with particular focus on neurodegenerative diseases, together with a short description of the state-of-the-art of methylation assays.

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The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases

Cited by 194 publications

References 106 publications

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

Redox Abnormalities as a Vulnerability Phenotype for Autism and Related Alterations in CNS Development

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

The ‘golden age’ of DNA methylation in neurodegenerative diseases

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