Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
Neurons exhibit a constitutive level of nuclear factor-κB (NF-κB) signaling and this pathway plays a significant role in neurite outgrowth, activity-dependent plasticity, and cognitive function. Transcription factor analysis was performed in a microarray data set profiled in four different brain regions (n=54 comparison group; n=53 schizophrenia (SZ)). An independent postmortem cohort was used for gene expression (n=24 comparison group; n=22 SZ), protein abundance (n=8 comparison group; n=8 SZ), and NF-κB nuclear activity (n=10 comparison group; n=10 SZ) quantification. Expression quantitative trait locus analysis was performed using publicly available data. Prepulse inhibition (PPI) of the acoustic startle reflex was tested in healthy individuals (n=690). Comparison of microarray data showed that NF-κB was among the transcription factors associated with the differential expression of genes in cases vs controls. NF-κB gene and protein levels and nuclear activation were significantly decreased in the superior temporal gyrus of patients with SZ. Upstream NF-κB genes related to translocation were significantly dysregulated in SZ. The gene expression levels of an NF-κB-associated importin (KPNA4: one of the proteins responsible for the translocation of NF-κB to the nucleus) was decreased in SZ and an SNP within the KPNA4 locus was associated with susceptibility to SZ, reduced KPNA4 expression levels and attenuated PPI of the startle reflex in healthy control subjects. These findings implicate abnormalities of the NF-κB signaling pathway in SZ and provide evidence for an additional possible mechanism affecting the translocation of NF-κB signaling to the nucleus.
biological psychiatry; gene expression; human postmortem; neurogenetics; neurophysiology; prepulse inhibition; schizophrenia / antipsychotics; transcription factor; postmortem; mRNA; superior temporal gyrus; prepulse inhibition; importin; transcription factor
Multiple lines of evidence in schizophrenia, from brain imaging, studies in postmortem brains, and genetic association studies, have implicated oligodendrocyte and myelin dysfunction in this disease. Recent studies suggest that oligodendrocyte and myelin dysfunction leads to changes in synaptic formation and function, which could lead to cognitive dysfunction, a core symptom of schizophrenia. Furthermore, there is accumulating data linking oligodendrocyte and myelin dysfunction with dopamine and glutamate abnormalities, both of which are found in schizophrenia. These findings implicate oligodendrocyte and myelin dysfunction as a primary change in schizophrenia, not only as secondary consequences of the illness or treatment. Strategies targeting oligodendrocyte and myelin abnormalities could therefore provide therapeutic opportunities for patients suffering from schizophrenia.
myelin; gene expression; genetic association; brain imaging; oligodendrocyte; synaptic plasticity; dopamine; glutamate
Abnormalities in oligodendrocyte (OLG) differentiation and OLG gene expression deficit have been described in schizophrenia (SZ). Recent studies revealed a critical requirement for Disrupted-in-Schizophrenia 1 (DISC1) in neural development. Transgenic mice with forebrain restricted expression of mutant human DISC1 (ΔhDISC1) are characterized by neuroanatomical and behavioral abnormalities reminiscent of some features of SZ. We sought to determine whether the expression of ΔhDISC1 may influence the development of OLGs in this mouse model.
OLG- and cell cycle-associated gene and protein expression were characterized in the forebrain of ΔhDISC1 mice during different stages of neurodevelopment (E15 and P1 days) and in adulthood.
The results suggest that the expression of ΔhDISC1 exerts a significant influence on oligodendrocyte differentiation and function, evidenced by premature OLG differentiation and increased proliferation of their progenitors. Additional findings showed that neuregulin 1 and its receptors may be contributing factors to the observed upregulation of OLG genes.
Thus, OLG function may be perturbed by mutant hDISC1 in a model system that provides new avenues for studying aspects of the pathogenesis of SZ.
Schizophrenia; disrupted-in schizophrenia 1; gene expression; oligodendrocyte; oligodendrogenesis; myelin; neuregulin
Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.
clozapine; pimozide; combination; schizophrenia; treatment non-response; biological psychiatry; clinical pharmacology/clinical trials; schizophrenia/antipsychotics; psychopharmacology; clozapine; pimozide; combination; schizophrenia; treatment non-response
Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double blind, placebo controlled, parallel designed 12 week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing PANSS total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.
clozapine; pimozide; combination; schizophrenia; treatment non-response
In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer’s disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus.
The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD.
Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p = .008) and NFTs (p = .047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p = .019), but the lower ratings of NFTs did not achieve statistical significance (p = .082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses.
These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.
Myelin abnormalities exist in schizophrenia leading to the hypothesis that oligodendrocyte dysfunction plays a role in the pathophysiology of the disease. The expression of the mRNA for the peripheral myelin protein-22 (PMP-22) is decreased in schizophrenia and recent genetic evidence suggests a link between PMP-22 and schizophrenia. While PMP-22 mRNA is found in both rodent and human brain it has been generally thought that no protein expression occurs. Here we show that PMP-22 protein is present in myelin isolated from adult mouse and human brain. These results suggest that PMP-22 protein likely plays a role in the maintenance and function of central nervous system (CNS) myelin and provide an explanation for why altered PMP-22 expression may be pathophysiologically relevant in a CNS disorder such as schizophrenia.
Myelin; Peripheral myelin protein-22; Schizophrenia
White matter abnormalities have been detected using diffusion tensor imaging (DTI) in a variety of locations in the brains of patients with schizophrenia. Studies that included first-episode patients report less severe or no abnormalities but more pronounced deficits in chronic patients. Here we investigated these abnormalities in a very large group of schizophrenia that had both large ranges in age and in duration of illness. A highly reproducible DTI-tractography technique was used to quantify the fractional anisotropy of the genu and splenium of the corpus callosum as well as the bilateral pyramidal tracts. We found a decline in fractional anisotropy that correlated with the duration of illness in the genu and splenium of the corpus callosum but not in the pyramidal tracts. The findings suggest that there are white matter tract-specific degenerative mechanisms that may be present at the point of illness onset and that progress throughout the illness.
Diffusion Tensor Imaging; Schizophrenia; Fiber Tracking
Considerable evidence based on the study of post-mortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, most (may be “the majority of the”?) biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using laser capture microdissection. The divisions studies were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut-2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei.
Schizophrenia; Thalamus; Neurons; Oligodendrocytes; Gene Expression
Several recent studies have found changes in the expression of genes functionally related to myelination and oligodendrocyte homeostasis in schizophrenia. These studies utilized microarrays and quantitative PCR (QPCR), methodologies which do not permit direct, unamplified examination of mRNA expression. In addition, these studies generally only examined transcript expression in homogenates of gray matter. In the present study, we examined the expression of myelination-related genes previously implicated in schizophrenia by microarray or QPCR. Using in situ hybridization, we measured transcript expression of 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), myelin-associated glycoprotein (MAG), transferrin (TF), quaking (QKI), gelsolin, myelin oligodendrocyte glycoprotein, v-erb-b2 erythroblastic leukemia viral oncogene homolog 3, erbb2 interacting protein, motility-related protein-1, SRY-box containing gene 10, oligodendrocyte transcription factor 2, peripheral myelin protein 22, and claudin-11 in both gray and white matter of the anterior cingulate cortex (ACC) in subjects with schizophrenia (n = 41) and a comparison group (n = 34). We found decreased expression of MAG, QKI, TF, and CNP transcripts in white matter. We did not find any differences in expression of these transcripts between medicated (n = 31) and unmedicated (n = 10) schizophrenics, suggesting that these changes are not secondary to treatment with antipsychotics. Finally, we found significant positive correlations between QKI and MAG or CNP mRNA expression, suggesting that the transcription factor QKI regulates MAG and CNP expression. Our results support the hypothesis that myelination and oligodendrocyte function are impaired in schizophrenia.
Alzheimer's disease is one of the most devastating brain disorders of elderly humans. It is an undertreated and under-recognized disease that is becoming a major public health problem. The last decade has witnessed a steadily increasing effort directed at discovering the etiology of the disease and developing pharmacological treatment. Recent developments include improved clinical diagnostic guidelines and improved treatment of both cognitive disturbance and behavioral problems. Symptomatic treatment mainly focusing on cholinergic therapy has been clinically evaluated by randomized, double-blind, placebo-controlled, parallel-group studies measuring performance-based tests of cognitive function, activities of daily living, and behavior. Cholinesterase inhibitors, including donepezil, tacrine, rivastigmine, and galantamine are the recommended treatment of cognitive disturbance in patients with Alzheimer's disease. The role of estrogen replacement, anti-inflammatory agents, and antioxidants is controversial and needs further study. Antidepressants, antipsychotics, mood stabilizers, anxiolytics, and hypnotics are used for the treatment of behavioral disturbance. Future directions in the research and treatment of patients with Alzheimer's disease include: applying functional brain imaging techniques in early diagnosis and evaluation of treatment efficacy; development of new classes of medications working on different neurotransmitter systems (cholinergic, glutamatergic, etc), both for the treatment of the cognitive deficit and the treatment of the behavioral disturbances; and developing preventive methods (amyloid p-peptide immunizations and inhibitors of β-secretase and γ-secretase).
Alzheimer's disease; etiology; epidemiology; apolipoprotein E4; cholinesterase inhibitor; antioxidant; anti-inflammatory agent; estrogen replacement therapy; behavioral disturbance