title: Genome-wide DNA methylation scan in major depressive disorder.
abstract: While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12-15% increased DNAm in MDD (p = 0.0002-0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.
authors.affiliation: Department of Pediatrics, Stanley Division of Developmental Neurovirology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Sarven
authors.initials: S
authors.lastname: Sabunciyan
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Irizarry
authors.forename: Michael
authors.initials: M
authors.lastname: Rongione
authors.forename: Maree J
authors.initials: MJ
authors.lastname: Webster
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufman
authors.forename: Peter
authors.initials: P
authors.lastname: Murakami
authors.forename: Andree
authors.initials: A
authors.lastname: Lessard
authors.forename: Robert H
authors.initials: RH
authors.lastname: Yolken
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
mesh_terms: D001921:Brain / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000235:genetics*; D044127:Epigenesis, Genetic; D056726:Genetic Association Studies; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human