Epigenomic Profiling Reveals DNA-Methylation Changes Associated with Major Psychosis
Jonathan Mill,Thomas Tang,Zachary Kaminsky,Tarang Khare,Simin Yazdanpanah,Luigi Bouchard,Luigi Bouchard,Peixin Jia,Abbas Assadzadeh,James M. Flanagan,James M. Flanagan,Axel Schumacher,Axel Schumacher,Sun Chong Wang,Sun Chong Wang,Arturas Petronis +15 more
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TLDR
This study uses CpG-island microarrays to identify DNA-methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder and reports evidence for a strong correlation between DNA methylation in the MEK1 gene promoter region and lifetime antipsychotic use in schizophrenia patients.Abstract:
Epigenetic misregulation is consistent with various non-Mendelian features of schizophrenia and bipolar disorder. To date, however, few studies have investigated the role of DNA methylation in major psychosis, and none have taken a genome-wide epigenomic approach. In this study we used CpG-island microarrays to identify DNA-methylation changes in the frontal cortex and germline associated with schizophrenia and bipolar disorder. In the frontal cortex we find evidence for psychosis-associated DNA-methylation differences in numerous loci, including several involved in glutamatergic and GABAergic neurotransmission, brain development, and other processes functionally linked to disease etiology. DNA-methylation changes in a significant proportion of these loci correspond to reported changes of steady-state mRNA level associated with psychosis. Gene-ontology analysis highlighted epigenetic disruption to loci involved in mitochondrial function, brain development, and stress response. Methylome network analysis uncovered decreased epigenetic modularity in both the brain and the germline of affected individuals, suggesting that systemic epigenetic dysfunction may be associated with major psychosis. We also report evidence for a strong correlation between DNA methylation in the MEK1 gene promoter region and lifetime antipsychotic use in schizophrenia patients. Finally, we observe that frontal-cortex DNA methylation in the BDNF gene is correlated with genotype at a nearby nonsynonymous SNP that has been previously associated with major psychosis. Our data are consistent with the epigenetic theory of major psychosis and suggest that DNA-methylation changes are important to the etiology of schizophrenia and bipolar disorder.read more
Citations
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DNA Methylation and Its Basic Function
Lisa D Moore,Thuc Le,Guoping Fan +2 more
TL;DR: The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
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Lasting epigenetic influence of early-life adversity on the BDNF gene.
TL;DR: An epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect is highlighted.
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Epigenome-wide association studies for common human diseases
TL;DR: This work discusses EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies, and how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
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DNA methylation profiles in monozygotic and dizygotic twins
Zachary Kaminsky,Thomas Tang,Sun Chong Wang,Sun Chong Wang,Carolyn Ptak,Gabriel Oh,Albert H.C. Wong,Laura A. Feldcamp,Carl Virtanen,Jonas Halfvarson,Curt Tysk,Allan F. McRae,Peter M. Visscher,Grant W. Montgomery,Irving I. Gottesman,Nicholas G. Martin,A. Petronis +16 more
TL;DR: The first annotation of epigenetic metastability of ∼6,000 unique genomic regions in MZ twins is provided, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.
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Genetics of bipolar disorder
TL;DR: It is almost certain that over the next few years bipolar susceptibility genes will be identified, which will have a major impact on the understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis.
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