Richard L. O'Reilly

Pharmacogenetic response to antidepressants in a multicase family with affective disorder

Eight members from two generations of a family met the DSM-III-R criteria for major depression. Four individuals had severe prolonged depressive disorders that did not respond to standard therapeutic doses of tricyclic and new generation antidepressants, but subsequently responded to the monoamine oxidase inhibitor, tranylcypromine. The literature on pharmacogenetics of the antidepressants is sparse. The pattern of selective response to tranylcypromine in this family supports the view that there is a familial tendency to respond to specific antidepressants or antidepressant groups. A history of response to a specific antidepressant in a relative may be helpful when selecting an antidepressant. Families demonstrating preferential response to specific psychotropics may be suitable pedigrees in which to perform linkage analysis using candidate genes related to the site of action of that psychotropic drug.

Site‐specific cytosine methylation in S‐COMT promoter in 31 brain regions with implications for studies involving schizophrenia

The catechol‐o‐methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB‐COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S‐COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated.

Involvement of gene-diet/drug interaction in DNA methylation and its contribution to complex diseases: from cancer to schizophrenia.

Most biological processes, including diseases, involve genetic and non‐genetic factors. Also, the realization of a genetic potential may depend on environmental factors by directly affecting the expression of gene(s). Exactly how different environmental factors affect gene expression is not well understood. One of the mechanisms may involve DNA methylation and thereby gene expression. Diet, chemicals, and metals are known to affect DNA methylation and other epigenetic processes but are just beginning to be elucidated. For example, methylation of cytosine(s) in the promoter region could prevent the binding of transcription factors or create binding sites for complexes that deacetylate neighboring histones that in turn compact the chromatin, encouraging a gene to become silent. This article will discuss DNA methylation as an epigenetic mechanism of gene regulation and examine how factors like diet, chemicals, and metals may affect DNA methylation. The effect of alterations in DNA methylation may include aberrant expression of genes or genomes and chromosomal instability, which in turn may contribute to the etiology of complex multifactorial diseases. A similar mechanism is now recognized in a number of cancers. There is also indirect evidence to suggest that methylation could apply to a number of complex diseases, including schizophrenia.

Ontogenetic de novo copy number variations (CNVs) as a source of genetic individuality: studies on two families with MZD twins for schizophrenia.

Genetic individuality is the foundation of personalized medicine, yet its determinants are currently poorly understood. One issue is the difference between monozygotic twins that are assumed identical and have been extensively used in genetic studies for decades [1]. Here, we report genome-wide alterations in two nuclear families each with a pair of monozygotic twins discordant for schizophrenia evaluated by the Affymetrix 6.0 human SNP array. The data analysis includes characterization of copy number variations (CNVs) and single nucleotide polymorphism (SNPs). The results have identified genomic differences between twin pairs and a set of new provisional schizophrenia genes. Samples were found to have between 35 and 65 CNVs per individual. The majority of CNVs (∼80%) represented gains. In addition, ∼10% of the CNVs were de novo (not present in parents), of these, 30% arose during parental meiosis and 70% arose during developmental mitosis. We also observed SNPs in the twins that were absent from both parents. These constituted 0.12% of all SNPs seen in the twins. In 65% of cases these SNPs arose during meiosis compared to 35% during mitosis. The developmental mitotic origin of most CNVs that may lead to MZ twin discordance may also cause tissue differences within individuals during a single pregnancy and generate a high frequency of mosaics in the population. The results argue for enduring genome-wide changes during cellular transmission, often ignored in most genetic analyses.

Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development.

Epidemiological data favors genetic predisposition for schizophrenia, a common and complex mental disorder in most populations. Search for the genes involved using candidate genes, positional cloning, and chromosomal aberrations including triplet repeat expansions have established a number of susceptibility loci and genomic sites but no causal gene(s) with a proven mechanism of action. Recent genome‐wide gene expression studies on brains from schizophrenia patients and their matched controls have identified a number of genes that show an alteration in expression in the diseased brains. Although it is not possible to offer a cause and effect association between altered gene expression and disease, such observations support a neurodevelopmental model in schizophrenia. Here, we offer a mechanism of this disease, which takes into account the role of developmental noise and diversions of the neural system. It suggests that the final outcome of a neural developmental process is not fixed and exact. Rather it develops with a variation around the mean. More important, the phenotypic consequence may cross the norm as a result of fortuitous and/or epigenetic events. As a result, a normal genotype may develop as abnormal with a disease phenotype. More important, susceptible genotypes may have reduced penetrance and develop as a normal phenocopy. The incidental episodes in neurodevelopment will explain the frequency of schizophrenia in most populations and high discordance of monozygotic twins.

Why Are Community Treatment Orders Controversial

The use of community treatment orders and other forms of mandatory outpatient treatment has been controversial. The debate on the appropriateness of compulsory treatment in the community addresses a volatile mix of clinical, social policy, legal, and philosophical issues. This paper describes the major sources of contention, outlines the position of the protagonists, and where possible, attempts to answer some of the questions raised and identify common ground.

Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis

The completion of the human genome sequence affords novel approaches to studies on contiguous gene deletion syndromes. These syndromes are caused by a deletion and loss of one copy of a set of contiguous genes on a given chromosome. Here, the syndromic phenotypes are often attributed to haploinsufficiency of a number of deleted genes. One such syndrome deals with deletion of 22q11.2. It is the most common microdeletion syndrome with a frequency of 1:4000 live births.1 This high frequency has been attributed to low copy repeats (LCR) on chromosome 22,2 with most cases (85-90%) representing de novo mutations. Also, the critical common region is relatively large (>1.5-3.0 Mb), may involve >30 genes, and there is no evidence of any correlation between the size of the deletion and the observed syndromic phenotypes.3 In fact, the clinical phenotype of the 22q11 deletion syndrome is characterised by extensive variability.4 It includes velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), and associated physical, developmental, neurological, and neuropsychiatric phenotypes. This phenotypic variability associated with the 22q11 deletion is an exception to all the other contiguous gene syndromes. More puzzling are recent reports that monozygotic twins (p>0.99) with 22q11 deletions have discordant phenotypes. In this discussion we will review all published cases of monozygotic twins concordant for del 22q11 and assess phenotypic discordance/concordance between them. More important, we will discuss an epigenetic explanation for their discordance that is compatible with modern molecular understanding of the human genome, the sequence features of this region of chromosome 22, and the “second hit” hypothesis involving genetic and/or epigenetic somatic events. ### Twin pair 1 Twin pair 15 was born to a 32 year old mother of European ancestry, at a gestational age of 38 weeks, weighing 2200 g (twin 1) and 2800 g (twin 2), apparently from a single placenta. …

Phenylethylamine and schizophrenia

1. The evidence that phenylethylamine (PEA) plays a role in the etiology of schizophrenia is reviewed. 2. PEA shares structural and physiological similarities with the amphetamines, the administration of which can induce a schizophrenia-like psychosis. 3. While there are a number of reports of high urinary PEA excretion in schizophrenic patients, the measurement of PEA in other body fluids and the measurement of phenylacetic acid (the major metabolite of PEA) has resulted in inconsistent findings. 4. The use of neuroleptic medication is a major confounding variable in most of the clinical studies. If PEA does have a role in the etiology of schizophrenia, the mechanism may involve PEAs ability to amplify dopamine responses.

Clinically significant differences among Canadian mental health acts.

Objectives:First, to highlight the major differences among mental health acts in different Canadian jurisdictions as they relate to involuntary admission criteria, treatment authorization, review and appeal procedures, and conditional leave and community treatment orders. Second, to analyze the impact of these differences on the care that individuals with mental illness receive.Method:We examined the mental health act provisions of all Canadian jurisdictions to determine how the clinical management of a typical case would differ among jurisdictions. We used a statement of principles for mental health legislation endorsed by the Canadian Psychiatric Association to guide the analysis. We confirmed interpretation of each act and its implementation through key informant contact in each province and territory.Results:We found clinically significant differences among the provinces and territories on all major components of their mental health acts.Conclusion:Provisions that prevent patients receiving appropriat...

Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

BackgroundChromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia.MethodsGenotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient.ResultsThis 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements.ConclusionThis Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion.