DNA Methylation as a Putative Mechanism for Reduced Dendritic Spine Density in the Superior Temporal Gyrus of Subjects with Schizophrenia

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. Elucidating the molecular mechanisms of this intermediate phenotype holds promise for understanding the pathogeneisis of schizophrenia, identifying 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. In the first postmortem brain study of the relationship of DNAm to DSD in schizophrenia, we tested the hypothesis that DNAm correlates with DSD in the human STG and that this relationship is disrupted in schizophrenia. We quantified DNAm at > 450,000 sites across the genome in the postmortem STG from 17 schizophrenia subjects and matched non-psychiatric control (NPC) subjects for which DSD measures were available. We found DNAm to correlate with DSD at more sites than expected by chance in NPC subjects (Panels A & B), but not in schizophrenia subjects (Panels C & D). From these data, we identified 2 candidate genes for mediating DSD abnormalities in schizophrenia: Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) and discs large, drosophila, homolog of, 1 (DLG1). DNAm-DSD correlations at 2 BAIAP2 sites (cg01276536 and cg23261327) reached a suggestive level of significance (Panel E), and one site for which the DNAm-DSD correlation differed significantly between subject groups (cg07756562) is located in the region 5 to DLG1 (Panel F). Our findings suggest that DNAm is an important upstream mechanism for generating normal DSD and that this mechanism is disrupted in schizophrenia. In future studies, we will test our hypothesis that reduced DSD in schizophrenia results, in part, from the altered transcription of multiple genes caused by alterations in DNAm.
McKinney B, Ding Y, Lewis DA, Sweet RA. DNA methylation as a putative mechanism for reduced dendritic spine density in the superior temporal gyrus of subjects with schizophrenia. Transl Psychiatry. 2017 Feb 14;7(2):e1032. doi: 10.1038/tp.2016.297. PMID: 28195572 [PubMed - in process]

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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