title: DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia.
abstract: Reduced dendritic spine density (DSD) in cortical layer 3 of the superior temporal gyrus (STG), and multiple other brain regions, is consistently observed in postmortem studies of schizophrenia (SZ). Elucidating the molecular mechanisms of this intermediate phenotype holds promise for understanding SZ pathophysiology, identifying SZ treatment targets and developing animal models. DNA methylation (DNAm), the addition of a methyl group to a cytosine nucleotide, regulates gene transcription and is a strong candidate for such a mechanism. We tested the hypothesis that DNAm correlates with DSD in the human STG and that this relationship is disrupted in SZ. We used the Illumina Infinium HumanMethylation450 Beadchip Array to quantify DNAm on a genome-wide scale in the postmortem STG from 22 SZ subjects and matched non-psychiatric control (NPC) subjects; DSD measures were available for 17 of the 22 subject pairs. We found DNAm to correlate with DSD at more sites than expected by chance in NPC, but not SZ, subjects. In addition, we show that the slopes of the linear DNAm-DSD correlations differed between SZ and NPC subjects at more sites than expected by chance. From these data, we identified 2 candidate genes for mediating DSD abnormalities in SZ: brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) and discs large, Drosophila, homolog of, 1 (DLG1). Together, these data suggest that altered DNAm in SZ may be a mechanism for SZ-related DSD reductions.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.|Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: McKinney
authors.affiliation: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.|Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.|Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.|Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Sweet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D001344:Autopsy; D016022:Case-Control Studies; D019175:DNA Methylation; D049229:Dendritic Spines / Q000473:pathology*; D000074288:Discs Large Homolog 1 Protein; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics* / Q000473:pathology; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D013702:Temporal Lobe / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119539:BAIAP2 protein, human; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins