 ORIGINAL RESEARCH ARTICLES
Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder
NL Johnston-Wilson, CD Sims, J-P Hofmann, L Anderson, AD Shore, EF Torrey, RH Yolken and the Stanley Neuropathology Consortium
Protein changes in the brains of patients with severe psychiatric disorders were undertaken using postmortem human frontal lobe tissue. A comparative study of proteins from 89 well-characterized tissue samples from schizophrenic, bipolar, depressed or unaffected individuals is presented. Two-dimensional gel electrophoresis combined with a multivariate analysis allowed the identification of eight spots that show statistically significant changes related to one or more psychiatric diseases. Two spots, identified as carbonic anhydrase I and fructose bisphosphate aldolase through electrospray mass spectroscopy, were increased in one or more diseases. Two spots, dihydropyrimidinase-related protein 2 and core 1 protein of the ubiquinol cytochrome c reductase complex, were decreased in one or more diseases. The remaining four spots were all identified as glial fibrillary acidic protein and were decreased in one or more diseases. The implications of these changes and the usefulness of this methodology are discussed.
Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment
V Arolt, M Rothermundt, K-P Wandinger, H Kirchner
Aberrations in the cytokine system that are typical for autoimmune disorders have been reported also in patients with schizophrenia, namely a decreased interleukin-2 production and increased levels of the soluble IL-2 receptor. In a longitudinal design, the authors studied the production of interferon-gamma and interleukin-2 in 29 patients with schizophrenia and matched healthy controls. The production of both IFN- and IL-2 was significantly lower in patients than in controls throughout the whole study period and was significantly correlated in controls as well as in patients with schizophrenia. No association between cytokine measurements and psychopathology could be found. These findings indicate that alterations in the cytokine system of patients with schizophrenia might resemble those in autoimmune disorders. These immunological abnormalities might be associated with the acute exacerbation rather than with a clinical subtype of schizophrenia.
Histamine H2 receptor gene variants: lack of association with schizophrenia
C Ito, S Morisset, M-O Krebs, J-P Olié, H Lôo, M-F Poirier, J-C Schwartz, J-M Arrang, L Lannfelt
A recent study reported the existence of several variants of the histamine H2-receptor (H2R) gene in a UK population. One of these variants (at position 649) was associated with schizophrenia. Using direct sequencing and restriction analysis, the authors analyzed the H2R gene variants in 53 Swedish and 140 French subjects. The variants reported in the UK population could not be found in either of the two populations. In contrast, three other polymorphisms were detected but were not described in the UK study. The first one was located within the coding region (position 543), the second was in the minimal promoter (position -592) and the third was in an enhancer element of the promoter (position -1018). The authors analyzed these polymorphisms in 88 schizophrenic patients and found that their incidence was not significantly different in this population. These findings may suggest an unexpected variability of the H2R gene polymorphisms in different geographical areas. They do not support an association of H2R gene variants with schizophrenia.
Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2)
T Yoshikawa, M Padigaru, JD Karkera, M Sharma, WH Berrettini, LE Esterling, SD Detera-Wadleigh
IMPA2 is a functional candidate gene located on chromosome 18p11.2, a region previously implicated in bipolar affective disorder and schizophrenia. The exon-intron structure and sequence of the potential promoter were determined. By sequencing the coding region and spice junctions, variants that were previously unreported were found. A trend for association with bipolar disorder was displayed by a silent mutation on codon 53 indicating that further analysis of this gene in independent samples is important.
A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients
G Sjøholt, AK Gulbrandsen, R Løvlie, JØ Berle, A Molven, VM Steen
Lithium is the drug of choice in the long-term treatment of manic-depressive illness, but the molecular mechanism(s) mediating its therapeutic effect are unknown. The enzyme inositol monophosphatase (IMPase) of the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Several studies have implicated a region on the short arm of chromosome 18 as a susceptibility locus for manic-depressive illness. Recently, the IMPA2 gene, which probably encodes an enzyme with IMPase function, was localized to the susceptibility region on 18p11.2. The authors have determined the genomic organization of the IMPA2 gene, and have performed a search for DNA variations (polymorphisms) in a material of bipolar patients. Their findings provide a necessary basis for further studies of the role of IMPA2 in the pathophysiology of manic-depressive illness and in determination of the response to lithium treatment.
Interaction between the serotonin transporter gene and neuroticism in cigarette smoking behavior
S Hu, CL Brody, C Fisher, L Gunzerath, ML Nelson, SZ Sabol, LA Sirota, SE Marcus, BD Greenberg, DL Murphy, DH Hamer
People who are depressed, anxious or impulsive are at high risk for nicotine addiction. Because this cluster of neurotic personality traits has previously been associated with a functional variation in the gene for the serotonin transporter, which is the target for anti-depressant drugs, the authors studied the joint effects of personality and serotonin transporter genotype in a population of 759 never, current and former smokers. The results show that smoking behavior is influenced by an interaction between neuroticism and the serotonin transporter gene. Neuroticism was positively correlated with current smoking and negatively associated with smoking cessation in individuals and siblings with poorly transcribed serotonin transporter genotypes, but not in those with more highly expressed genotypes. Individuals with both a poorly expressed genotype and a high level of neuroticism had the greatest difficulty in quitting smoking. These data suggest that it may be possible to individually tailor smoking cessation programs by taking into account a person's genes and personality.
Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence
C Lerman, NE Caporaso, J Audrain, D Main, NR Boyd, PG Shields
Genetic factors appear to influence the chances that a person will become addicted to nicotine. In this study, the authors examined whether a specific gene, the serotonin transporter gene, is involved in nicotine dependence and smoking practices. The serotonin transporter gene affects levels of a brain chemical called serotonin which plays a role in mood. It has a long form and a short form. The short form has been related in previous studies to anxiety-related personality traits. In the present study, the authors conducted genetic, personality, and smoking assessments of 185 smokers. They found that people who had high levels of neuroticism (an anxiety-related personality trait) were more likely to be dependent upon nicotine, if they had at least one copy of the short form of the serotonin gene. However, this trait did not relate to nicotine dependence in persons with the long form of this gene. These results suggest that personality traits and genetic factors may have interacting effects on nicotine addiction. This information may be useful to identify smokers who are most least likely to benefit from drug treatments for smoking cessation.
Possible association of the short allele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide
B Bondy, A Erfurth, S de Jonge, M Krüger, H Meyer
According to a recently formulated hypothesis the vulnerability for suicidal behaviour results from an interaction of several risk factors, such as acute psychiatric illness, substance abuse, adverse life events or family crisis and genetic factors. Since disturbances in serotonergic transmission are widely associated with impulsive, violent behaviour, the promoter region of the serotonin transporter gene (5-HTTLPR) is receiving increasing interest in psychiatric genetic research. The authors examined if the L- or S-allele of the 5-HTTLPR might be associated with suicidality in DNAs from 58 suicide victims (with unknown psychiatric diagnosis; most of them committing violent suicide) and 110 healthy controls. They found a highly significant excess of L/S and S/S in suicide victims as compared to normal controls. Although still preliminary, these results suggest that the 5-HTTLPR may contribute to autoaggressive behaviour and violent suicide, irrespectively from clinical diagnosis.
Glucocorticoid receptor alpha and beta isoforms are not mutated in bipolar affective disorder
P Moutsatsou, A Tsolakidou, G Trikkas, C Troungos, CE Sekeris
Bipolar affective disorder is a stress-related illness causing severe social problems. Investigations yielding insights into the mechanisms underlying the pathophysiology of the disease, leading to appropriate therapies, is, therefore, a major public health priority. A genetic predisposition is implicated and a number of candidate genes have been evaluated but have not yielded positive findings. Experimental findings reporting changes in the binding characteristics of the glucocorticoid receptor (GR) suggest the possible involvement of the GR in the aetiopathology of this disease. In this study the authors searched for possible mutations of the GR gene by applying molecular methodology; no such mutations could be detected. These results, in conjunction with recent findings supporting that other regulatory agents can modulate GR action, imply the possible involvement of such agents as aetiopathologic factors in bipolar disease.
Muscarinic and receptor mRNA in the human caudate-putamen: no change in m1 mRNA in schizophrenia
B Dean, JM Crook, G Pavey, K Opeskin, DL Copolov
The authors have suggested there is a decrease in the muscarinic1 and muscarinic2 receptor in the caudate-putamen from schizophrenic subjects. They have now shown that the mRNA for the muscarinic2 receptor in the human caudate-putamen is below the level detectable by in situ hybridisation. This would be consistent with the muscarinic2 receptor being an autoreceptor in the human caudate-putamen, its mRNA being located in the cell bodies of innervating neurons that are outside the caudate-putamen. They have also shown a decreased level of radioligand binding to the muscarinic2 receptor in caudate-putamen from the schizophrenic subjects that was not accompanied by changes in the levels of mRNA for that receptor. These data would not support the proposal that the decrease in muscarinic1 receptors in caudate-putamen from subjects with schizophrenia is due to a decreased level of expression.
Comparative sequencing of the proneurotensin gene and association studies in schizophrenia
J Austin, B Hoogendoorn, P Buckland, G Speight, A Cardno, T Bowen, N Williams, G Spurlock, R Sanders, L Jones, K Murphy, M McCarthy, P McGuffin, MJ Owen, MC O'Donovan
Neurotensin (NT) is a naturally occurring modulator of dopaminergic neurotransmission. As the leading hypothesis of the origins of schizophrenia involves dysfunctional dopaminergic neurotransmission, it has been proposed that abnormal NT function might be a mechanism contributing to this disorder. In this study, the authors have sought to examine the role of NT in schizophrenia by searching for DNA variation in the gene encoding NT in subjects with schizophrenia. They detected three sequence variants in NT, two in schizophrenic subjects and one in a subject with bipolar affective disorder. Neither of the two variants showed significant evidence for association with schizophrenia. They conclude that abnormal NT function is unlikely to be a primary cause of increased susceptibility to schizophrenia, although it is still possible that altered NT function might mediate the effects of the primary causes or the effects of therapeutic agents.
Confirmation of the association between bleomycin hydrolase genotype and Alzheimer's disease
A Papassotiropoulos, M Bagli, F Jessen, C Frahnert, ML Rao, W Maier, R Heun
The histopathological hallmark of Alzheimer's disease (AD) is the formation of aggregates of  -amyloid peptide (A). A derives from its precursor protein (APP) via cleavage by yet unidentified enzymes (so called beta- and gamma secretases). The enzyme bleomycin hydrolase (BH) has been discussed as a possible beta-secretase. Recently Montoya and colleagues showed that a polymorphism of the gene encoding BH is associated with the risk for AD; however in a subsequent study Farrer and colleagues failed to show this association. In this study the authors addressed the same question using a homogenous sample of German AD patients and control subjects and could replicate the finding of Montoya et al. However, the association was observed in carriers of the apolipoprotein E- 4 allele (apoE-4) and not, as reported by Montoya, in non-carriers of this allele. Additional studies should be undertaken to explore the relationship between AD, BH and apoE.
Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs
Y Osher, D Hamer, J Benjamin
The neurotransmitter serotonin is thought to play a key role in anxiety and depression and is the target for a very popular class of psychiatric drugs. This study examined the relationship between a functional polymorphism in the regulatory region of the serotonin transporter gene and anxiety-related personality traits in normal sibling pairs from Israel. Using two different psychological tests and two different analytical methods ¾ one which examines the overall relationship between these traits and individuals with differing forms of the gene, and another which studies the differences between siblings who have different forms of the gene ¾ additional evidence was obtained that this gene affects normal temperament and personality traits. Persons who have the 'short' form of the gene tend to be more anxious, worried, fearful, pessimistic, and cautious than people who have only the 'long' form.
A polymorphic region in the human transcription factor AP-2 gene is associated with specific personality traits
M Damberg, H Garpenstrand, J Alfredsson, J Ekblom, K Forslund, G Rylander, L Oreland
The authors suggest a novel approach in the elucidation of the genetic part of psychiatric disorders and personality, ie to identify transcription factor genes as candidate genes in psychiatric disorders and personality. In support for this notion, they show, in the current study, that the personality traits muscular tension, guilt, somatic anxiety, psychastenia and indirect aggression, as estimated by the Karolinska Scales of Personality (KSP) are significantly related to transcription factor AP-2 genotype. Since important genes encoding proteins in the dopaminergic and serotonergic system have binding sites for AP-2 in their regulatory regions, one might speculate that the expression of different isoforms of AP-2 influences mood and personality, not only due to their role during development of the brain, but also due to their function during adulthood.
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