Gene/Protein Disease Symptom Drug Enzyme Compound
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Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.
Hum Mol Genet 2001 Dec 01
PMID:A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. 1174 36

Schizophrenia is a complex neurodevelopmental disorder characterized by mental dysfunction across multiple domains of the brain. It affects 1% of world's general population and the nature of neurobiological lesions in the schizophrenic brain are not known. Although the exact etiology of the disorder is not understood, twin, family and adoption studies have provided consistent evidence that genetic factors play a major role in the pathogenesis. A genome-wide genetic linkage screen identified loci on chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 13, 15, 18, 22 and the X with positive lod scores, thus excluding a single major locus for schizophrenia. Association studies have generated disappointing results in identifying the susceptible DNA sequence variants and the anticipation hypothesis on trinucleotide repeat expansion provided equivocal results or lack of enthusiasm. Although there are no biological markers at present, the recent finding that human endogenous retrovirus is activated in cerebrospinal fluid as well as in the postmortem schizophrenic brain may change our understanding of the etiopathogenesis of this disease. Meanwhile, treatment with newly developed anti-psychotic drugs combined with educational and cognitive rehabilitation procedure may help the patients to cope with the illness.
Int J Mol Med 2002 Mar
PMID:Schizophrenia: a genetic perspective (review). 1183 24

The genetic etiology of schizophrenia, a common and debilitating psychiatric disorder, is supported by a wealth of data. Review of the current findings suggests that considerable progress has been made in recent years, with a number of chromosomal regions consistently implicated by linkage analysis. Three groups have shown linkage to 1q21-22 using similar models, with HLOD scores of 6.5, 3.2, and 2.4. Other replicated loci include 13q32 that has been implicated by two independent groups with significant HLOD scores (4.42) or NPL values (4.18), and 5pl4.1-13.1, 5q21-33, 8p2l-22, and 10p11-15, each of which have been reported as suggestive by at least three separate groups. Different studies have also replicated evidence for a modest number of candidate genes that were not ascertained through linkage. Of these, the greatest support exists for the DRD3 (3q13.3), HTR2A (13q14.2), and CHRNA7 (15q13-q14) genes. The refinement of phenotypes, the use of endophenotypes, reduction of heterogeneity, and extensive genetic mapping have all contributed to this progress. The rapid expansion of information from the human genome project will likely further accelerate this progress and assist in the discovery of susceptibility genes for schizophrenia. A greater understanding of disease mechanisms and the application of pharmacogenetics should also lead to improvements in therapeutic interventions.
Cell Mol Life Sci 2002 Feb
PMID:Recent advances in the genetics of schizophrenia. 1191 47

Manic-depressive illness is a common psychiatric disorder with complex etiology that likely involves multiple genes and non-genetic influences. The uncertain path to gene discovery has spurred considerable debate over genetic findings and gene-finding strategies. In this article, I review the main findings, with a focus on: (1) putative linked loci on chromosomes 1q31-32, 4p16, 6pter-p24, 10p14, 10q21-26, 12q23-24, 13q31-32, 18p11, 18q21-23, 21q22, 22q11-13, and Xq24-28; and (2) association studies with candidate genes, dynamic mutations, mitochondrial mutations, and chromosomal aberrations. Although no gene has been identified, promising findings are emerging. I then discuss the challenges and opportunities ahead, with special emphasis on gene-finding methods-in particular, questions pertaining to phenotype definition, linkage and association mapping, gene markers, sampling, study population, multigene systems, lessons from other disorders, animal models, and bioinformatics. The progress to date, together with rapid advances in genomics, analytical and computational methods, and bioinformatics, holds promise for new insights into the genetics of manic-depression, in the new millennium.
Mol Psychiatry 2002
PMID:Manic-depression genes and the new millennium: poised for discovery. 1198 78

Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions.(1) Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity.(2-7) Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence.(8-11) We performed an association study between the ser310ala GRIK3polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia.
Mol Psychiatry 2002
PMID:Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. 1198 86

Mental disorders are highly prevalent and often difficult to diagnose. There is a significant gap between advances in their pharmacotherapy and the present lack of objective biologic tests for diagnosis. The special complexity of diagnosis in psychiatry is related to the absence of objective diagnostic "gold standards", co-morbidity, heterogeneity and equifinality, quantitative trait loci, and locus heterogeneity. Here, we review recent findings relating to diagnostic, pathophysiological, and linkage markers for mood disorders at the biochemical level involving monoamine neurotransmitters, hormones, and signal-transducing G proteins. Identification of biological diagnostic markers could enable segregating mood disorders to several biologically different subtypes. New-era methods and strategies involving genomics, proteomics, multi-marker approach and single nucleotide polymorphisms have the potential to revolutionize future diagnosis in psychiatry.
Trends Mol Med 2002 Jun
PMID:Toward molecular diagnostics of mood disorders in psychiatry. 1206 16

Glucocorticoid receptors (GR) mediate the direct effects of glucocorticoids released in response to stress and the regulation of the hypothalamic-pituitary-adrenocortical (HPA) system through a negative feedback mechanism. Individuals with major mental illness, who often exhibit hypercortisolemia, may have down-regulated levels of GR mRNA. In situ hybridization for GR mRNA was performed on post-mortem specimens from patients suffering from depression, bipolar disorder, schizophrenia and from normal controls (n = 15 per group). In frontal cortex, GR mRNA levels were decreased in layers III-VI in the subjects with depression and schizophrenia. In inferior temporal cortex, GR mRNA levels were decreased in layer IV in all three diagnostic groups. In the entorhinal cortex, GR mRNA levels were decreased in layers III and VI in the bipolar group. In hippocampus, GR mRNA levels were reduced in the dentate gyrus, CA(4), CA(3) and CA(1) in the schizophrenia group. In the subiculum, GR mRNA levels were reduced in the bipolar group. These results suggest that GR dysregulation occurs in all three major psychiatric illnesses with variability according to anatomical site. The severity and heterogeneity of this reduction may underlie some of the clinical heterogeneity seen in these disorders.
Mol Psychiatry 2002
PMID:Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders. 1239 52

Schizophrenia, the most severe psychiatric disorder, is characterized by heterogeneity of clinical signs, often categorized into positive and negative symptoms. Among a wide array of competing biological mechanisms, altered cerebral energy metabolism and mitochondrial dysfunction have been suggested to play an important role in the pathophysiology of schizophrenia. In this study we investigated mitochondrial complex I in platelets of 113 schizophrenic patients divided into three groups (acute psychotic episode, chronic active state and residual schizophrenia) and 37 control subjects. Complex I was analysed at the level of enzymatic activity, mRNA and protein levels by enzyme kinetics, RT-PCR and Western blot analyses, respectively. Complex I activity in platelets of schizophrenic patients altered with disease state presenting high specificity and sensitivity. Thus, increased activity was associated with psychotic symptomology, while its decrease was observed in patients with residual schizophrenia. The relationship between the clinical state and complex I activity in schizophrenia was further supported by its positive correlation with the severity of patients' positive symptoms assessed by clinical ratings. In addition, similar alterations were observed at the levels of mRNA and protein of the 24- and 51-kDa iron-sulfur flavoprotein subunits of the complex. Taken together these results point to the potential of platelet complex I to turn into a reliable novel marker for schizophrenia. At present, definitive diagnosis depends only on descriptive behavioral and symptomatic information, therefore a peripheral measurable specific marker will contribute to diagnosis and monitoring of the disease.
Mol Psychiatry 2002
PMID:State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia. 1239 53

Schizophrenia is a major psychiatric disorder which is hypothesized to result from abnormal neurodevelopment or neural changes in adulthood and possibly associated with altered gene expression. To search for genes overexpressed in schizophrenia, cDNA library subtractive hybridization experiments between post-mortem human frontal cerebral cortices from schizophrenia individuals and neurological controls were carried out. One of the genes over-expressed in schizophrenia was identified as Nogo (also known as reticulon 4, RTN4, NI 250, or RTN-X), a myelin-associated protein which inhibits the outgrowth of neurites and nerve terminals. The elevated expression of Nogo mRNA in schizophrenia was confirmed by quantitative reverse transcription-polymerase chain reaction studies: 16.5 pg Nogo cDNA/microg total RNA in schizophrenia, and 10.2 pg Nogo cDNA/microg total RNA in controls (n=7; P=0.01, t-test for n<30). To identify possible polymorphisms in this gene, the Nogo nucleotide sequence was determined in a series of schizophrenia and control samples. The Nogo mRNA was found to contain a CAA insert polymorphism in the 3'-untranslated region. The prevalence of individuals homozygous for this CAA insert was significantly higher in schizophrenia compared to controls in genomic DNA samples extracted from post-mortem brain and blood samples: 17/81 or 21% in schizophrenia and 2/61 or 3% in controls (P=0.0022, chi(2)- and Fisher's exact-tests). Because the 3'-untranslated regions of eukaryotic genes are known to regulate gene expression, the increased frequency of the Nogo CAA insert in schizophrenia may contribute to abnormal regulation of Nogo gene expression, and may indicate a role for Nogo in disturbed neurodevelopment in schizophrenia.
Brain Res Mol Brain Res 2002 Nov 15
PMID:Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. 1242 46

Mental disorders are highly prevalent and often difficult to diagnose. Although significant advances have been achieved in medication for mental disorders, the diagnosis and treatment monitoring of these disorders remain in a static situation. The absence of objective diagnostic 'gold standards', derives from the special complexity of diagnosis in psychiatry. Heterotrimeric G-proteins are crucial elements in post-receptor information transduction. These proteins have been implicated in the biochemical mechanism of action of drugs used to treat psychiatric disorders. G-protein measurements have unravelled a differential pattern characteristic of each of the major mental disorders. The accumulated data supports the potential use of G-protein measures as state-dependent markers for the biochemical diagnosis of mental disorders and as aid in the biochemical monitoring of the response to a specific treatment.
Expert Rev Mol Diagn 2003 Jan
PMID:Application of G-proteins in the molecular diagnosis of psychiatric disorders. 1252 65


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