Over the past year, we focused on several candidate genes for schizophrenia and affective disorders, and studied expression of multiple transcripts of these genes and their associations with schizophrenia risk-associated genotypes. For instance, for a DARPP-32 gene, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex DLPFC, hippocampus, and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders. We also examined copy number variations (CNVs) associated with diverse neurodevelopmental behavioral disorders. We analyzed 1M SNP genotype arrays (Illumina BeadArrays) for evidence of previously reported recurrent CNVs and enriched genome wide CNV burden in DNA from 600 brains, including 441 individuals with various psychiatric diagnoses. We explored gene expression in the dorsolateral prefrontal cortex in selected cases with CNVs and in other subjects using Illumina BeadArrays (568 subjects in total), and additionally in 66-92 subjects using quantitative real-time PCR. CNVs in previously reported genomic regions were identified in 4/193 patients with the diagnosis of schizophrenia (1q21.1, 11q25, 15q11.2, 22q11), 4/238 patients with mood disorders (11q25, 15q11.2, 22q11), and 1/10 patients with autism (2p16.3). No evidence of increased genome wide CNV burden was observed in cases with schizophrenia or mood disorders although the study is underpowered to observe rare events. mRNA expression patterns suggested incomplete molecular penetrance of observed CNVs, particularly in the duplications. Our data confirm in brain DNA the presence of certain recurrent CNVs in a small percentage of patients with psychiatric diagnoses. Finally, we explored epigenetic changes during development of the human prefrontal cortex (PFC), a mastermind of the brain, which is one of the last brain regions to mature. It is also a region implicated in schizophrenia and other major mental disorders. To investigate the role of epigenetics in the development of PFC we examined DNA methylation in 14,500 genes at 27,000 CpG loci focused on 5 promoter regions in 108 subjects ranging from fetal to old age. DNA methylation in the PFC shows unique temporal patterns across life. The fastest changes occur during the prenatal period, slow down markedly after birth and continue to slow further with aging. At the genome level, the transition from fetal to postnatal life is typified by a reversal of direction, from demethylation prenatally to increased methylation postnatally. DNA methylation is strongly associated with genotypic variants and correlates with expression of a subset of genes, including genes involved in brain development and in de novo DNA methylation. Our results indicate that promoter DNA methylation in the human PFC is a highly dynamic process modified by genetic variance and regulating gene transcription. We have made additional discovery by the scientists possible by using a stand-alone application BrainCloudMeth created by our team. We have conducted several investigations using postmortem human brain specimens focused primarily on understanding the pathophysiology of SZ in addition to other complex neuropsychiatric disorders. In addition to our own studies, the Section continues to provide postmortem human brain tissues to researchers and labs within and outside NIH.

Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2013
Total Cost
$767,073
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
Morita, Yukitaka; Callicott, Joseph H; Testa, Lauren R et al. (2014) Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia. J Neurosci 34:4929-40
Akula, N; Barb, J; Jiang, X et al. (2014) RNA-sequencing of the brain transcriptome implicates dysregulation of neuroplasticity, circadian rhythms and GTPase binding in bipolar disorder. Mol Psychiatry 19:1179-85
Kunii, Y; Hyde, T M; Ye, T et al. (2013) Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. Mol Psychiatry :
Blasi, Giuseppe; Napolitano, Francesco; Ursini, Gianluca et al. (2013) Association of GSK-3ýý genetic variation with GSK-3ýý expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia. Am J Psychiatry 170:868-76
Buerlein, Ross C; Hyde, Thomas M; Lipska, Barbara K et al. (2009) A comparison of human brain dissection by drill versus saw on nucleic acid quality. J Neurosci Methods 179:68-70
Huffaker, Stephen J; Chen, Jingshan; Nicodemus, Kristin K et al. (2009) A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med 15:509-18
Sartorius, Leah J; Weinberger, Daniel R; Hyde, Thomas M et al. (2008) Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP. Neuropsychopharmacology 33:2626-34
Lehrmann, Elin; Afanador, Zoan R; Deep-Soboslay, Amy et al. (2008) Postmortem diagnosis and toxicological validation of illicit substance use. Addict Biol 13:105-17
Mitkus, Shruti N; Hyde, Thomas M; Vakkalanka, Radhakrishna et al. (2008) Expression of oligodendrocyte-associated genes in dorsolateral prefrontal cortex of patients with schizophrenia. Schizophr Res 98:129-38
Halim, Nader D; Lipska, Barbara K; Hyde, Thomas M et al. (2008) Increased lactate levels and reduced pH in postmortem brains of schizophrenics: medication confounds. J Neurosci Methods 169:208-13

Showing the most recent 10 out of 15 publications