title: Epigenomic profiling reveals DNA-methylation changes associated with major psychosis.
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.
authors.affiliation: Krembil Family Epigenetic Laboratory, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, M5T 1R8, Canada.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.forename: Thomas
authors.initials: T
authors.lastname: Tang
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kaminsky
authors.forename: Tarang
authors.initials: T
authors.lastname: Khare
authors.forename: Simin
authors.initials: S
authors.lastname: Yazdanpanah
authors.forename: Luigi
authors.initials: L
authors.lastname: Bouchard
authors.forename: Peixin
authors.initials: P
authors.lastname: Jia
authors.forename: Abbas
authors.initials: A
authors.lastname: Assadzadeh
authors.forename: James
authors.initials: J
authors.lastname: Flanagan
authors.forename: Axel
authors.initials: A
authors.lastname: Schumacher
authors.forename: Sun-Chong
authors.initials: SC
authors.lastname: Wang
authors.forename: Arturas
authors.initials: A
authors.lastname: Petronis
mesh_terms: D000328:Adult; D001483:Base Sequence; D001714:Bipolar Disorder / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005796:Genes; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D012559:Schizophrenia / Q000235:genetics*