Albert H.C. Wong

DNA methylation profiles in monozygotic and dizygotic twins

Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of ∼6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 × 10−294). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

Schizophrenia: from phenomenology to neurobiology.

Schizophrenia is a common and debilitating illness, characterized by chronic psychotic symptoms and psychosocial impairment that exact considerable human and economic costs. The literature in electronic databases as well as citations and major articles are reviewed with respect to the phenomenology, pathology, treatment, genetics and neurobiology of schizophrenia. Although studied extensively from a clinical, psychological, biological and genetic perspective, our expanding knowledge of schizophrenia provides only an incomplete understanding of this complex disorder. Recent advances in neuroscience have allowed the confirmation or refutation of earlier findings in schizophrenia, and permit useful comparisons between the different levels of organization from which the illness has been studied. Schizophrenia is defined as a clinical syndrome that may include a collection of diseases that share a common presentation. Genetic factors are the most important in the etiology of the disease, with unknown environmental factors potentially modulating the expression of symptoms. Schizophrenia is a complex genetic disorder in which many genes may be implicated, with the possibility of gene-gene interactions and a diversity of genetic causes in different families or populations. A neurodevelopmental rather than degenerative process has received more empirical support as a general explanation of the pathophysiology, although simple dichotomies are not particularly helpful in such a complicated disease. Structural brain changes are present in vivo and post-mortem, with both histopathological and imaging studies in overall agreement that the temporal and frontal lobes of the cerebral cortex are the most affected. Functional imaging, neuropsychological testing and clinical observation are also generally consistent in demonstrating deficits in cognitive ability that correlate with abnormalities in the areas of the brain with structural abnormalities. The dopamine and other neurotransmitter systems are certainly involved in the treatment or modulation of psychotic symptoms. These broad findings represent the distillation of a large body of disparate data, but firm and specific findings are sparse, and much about schizophrenia remains unknown.

Polymorphisms in dopamine receptors: what do they tell us?

Many genetic studies have focussed on dopamine receptors and their relationship to neuropsychiatric disease. Schizophrenia, bipolar disorder, and substance abuse have been the most studied, but no conclusive linkage or association has been found. The possible influence of dopamine receptor variants on drug response has not received as much attention. While there is some evidence that polymorphisms and mutations in dopamine receptors can alter functional activity and pharmacological profiles, no conclusive data link these gene variants to drug response or disease. The lack of unequivocal findings may be related, in part, to the subtle changes in receptor pharmacology that these polymorphisms and mutations mediate. These subtle effects may be obscured by the influence of genes controlling drug metabolism and kinetics. Further insight into the pharmacogenetics of dopamine receptors may require not just more studies, but novel approaches to the study of complex genetic traits and diseases.

5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary

The 5-methylcytosine (5-mC) derivative 5-hydroxymethylcytosine (5-hmC) is abundant in the brain for unknown reasons. Here we characterize the genomic distribution of 5-hmC and 5-mC in human and mouse tissues. We assayed 5-hmC by using glucosylation coupled with restriction-enzyme digestion and microarray analysis. We detected 5-hmC enrichment in genes with synapse-related functions in both human and mouse brain. We also identified substantial tissue-specific differential distributions of these DNA modifications at the exon-intron boundary in human and mouse. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural contexts. This pattern was replicated in multiple independent data sets and with single-molecule sequencing. Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain.

Serine racemase is associated with schizophrenia susceptibility in humans and in a mouse model

Abnormal N-methyl-d-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. d-serine is an important NMDAR modulator, and to elucidate the role of the d-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and dramatically reduced d-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were exacerbated by an NMDAR antagonist and ameliorated by d-serine or the atypical antipsychotic clozapine. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Transcript levels altered by the Srr mutation were also normalized by d-serine or clozapine treatment. Furthermore, analysis of SRR genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant Srr function and diminished d-serine may contribute to schizophrenia pathogenesis.

The role of BDNF in the pathophysiology and treatment of schizophrenia

Brain derived neurotrophic factor (BDNF) has been associated with the pathophysiology of schizophrenia (SCZ). However, it remains unclear whether alterations in BDNF observed in patients with SCZ are a core part of disease neurobiology or a consequence of treatment. In this manuscript we review existing knowledge relating the function of BDNF to synaptic transmission and neural plasticity and the relationship between BDNF and both pharmacological and non-pharmacological treatments for SCZ. With regards to synaptic transmission, exposure to BDNF or lack of this neurotrophin results in alteration to both excitatory and inhibitory synapses. Many authors have also evaluated the effects of both pharmacological and non-pharmacological treatments for SCZ in BDNF and despite some controversial results, it seems that medicated and non-medicated patients present with lower levels of BDNF when compared to controls. Further data suggests that typical antipsychotics may decrease BDNF expression whereas mixed results have been obtained with atypical antipsychotics. The authors found few studies reporting changes in BDNF after non-pharmacological treatments for SCZ, so the existing evidence in this area is limited. Although the study of BDNF provides some new insights into understanding of the pathophysiology and treatment of SCZ, additional work in this area is needed.

Disc1 Point Mutations in Mice Affect Development of the Cerebral Cortex

Disrupted-in-Schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.

Contributions of the d-serine pathway to schizophrenia

The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on D-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating D-serine, NMDA receptors and related molecules, such as D-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered D-serine pathway genes and from preliminary clinical trials with D-serine itself or compounds modulating the D-serine pathway. Abnormalities in D-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the D-serine pathway may significantly improve outcomes for many schizophrenia patients.

Not really identical: Epigenetic differences in monozygotic twins and implications for twin studies in psychiatry†

Classical twin studies in the field of psychiatry generally fall into one of two categories: (1) those designed to identify environmental risk factors causing discordance in monozygotic (MZ) twins and (2) those geared towards identifying genetic risk factors. However, neither environment nor differences in DNA sequence can fully account for phenotypic discordance among MZ twins. The field of epigenetics – DNA modifications that can affect gene expression – offers new models to understand discordance in MZ twins. In the past, MZ twins were regarded as genetically‐identical controls for differing environmental conditions. In contrast, the evolving current concept is that epigenetic differences between MZ twins may modulate differences in diverse phenotype, from disease to personality. In this article, we review some twin studies, and discuss the dynamic interactions between stochastic, environmental, and epigenetic variables that influence neurobiological phenotypes.

Maternal Immune Activation during Gestation Interacts with Disc1 Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice

Schizophrenia is thought to result from interactions between susceptible genotypes and environmental risk factors. DISC1 is an important gene for schizophrenia and mood disorders based on both human and animal studies. In the present study we sought to investigate interactions between two distinct point mutations in the mouse Disc1 gene (L100P and Q31L) and maternal immune activation (MIA) during pregnancy with polyinosinic:polycytidylic acid (polyI:C). PolyI:C given at 5 mg/kg impaired cognitive and social behavior in both wild-type (WT) and Disc1-Q31L+/− offspring, and reduced prepulse inhibition at 16 but not 8 weeks of age. Disc1-L100P+/− mutants were more sensitive to MIA than WT or Disc1-Q31L+/− mice. Interleukin-6 (IL-6) is a critical cytokine for mediating the behavioral and transcriptional effects of polyI:C. We found a more pronounced increase of IL-6 in response to polyI:C in fetal brain in Disc1-L100P+/− mice compared with WT or Disc1-Q31L+/− mice. Coadministration of an anti-IL-6 antibody with polyI:C reversed schizophrenia-related behavioral phenotypes in Disc1-L100P+/− mice. In summary, we found specific interactions between discrete genetic (Disc1-L100P+/−) and environmental factors (MIA) that exacerbate schizophrenia-related phenotypes. IL-6 may be important in the pathophysiology of this interaction.