There is growing interest in the genetic analysis of schizophrenia using endophenotypes rather than clinical diagnosis or symptom dimensions. Endophenotypes could be alternative phenotypes for the clinical phenotypes. With their intermedicate and quantitative characteristics, endophenotypes could be functionally important links in the pathways between the genetic variation and clinical expression of the disorder. In this regard, the neurophysiological and neurocognitive endophenotypes used in the genetic analysis of schizophrenia have been reviewed.
Diagnosis ; Endophenotypes* ; Genetic Variation ; Genetics* ; Phenotype ; Schizophrenia*

OBJECTIVE: DISC1 gene is one of the main candidate genes for schizophrenia since it has been associated to the illness in several populations. Moreover, variations in several DISC1 polymorphisms, and in particular Ser704Cys SNP, have been associated in schizophrenic patients to structural and functional modifications in two brain areas (pre-frontal cortex and hippocampus) that play a central role in the genesis of psychotic symptoms. This study tested the association between Ser704Cys DISC1 polymorphism and the clinical onset of psychosis. METHODS: Two hundred and thirteen Caucasian drug-naive patients experiencing a first episode of non-affective psychosis were genotyped for rs821616 (Ser704Cys) SNP of the DISC1 gene. The clinical severity of the illness was assessed using SAPS and SANS scales. Other clinical and socio-demographic variables were recorded to rule out possible confounding effects. RESULTS: Patients homozygous for the Ser allele of the Ser704Cys DISC1 SNP had significantly (p<0.05) higher rates at the positive symptoms dimension (SAPS-SANS scales) and hallucinations item, compared to Cys carriers. CONCLUSION: DISC1 gene variations may modulate the clinical severity of the psychosis at the onset of the disorder.
Alleles ; Brain ; Genetics ; Hallucinations ; Humans ; Psychotic Disorders* ; Schizophrenia ; Weights and Measures

Chromosomes, Human, Pair 22 ; genetics ; DiGeorge Syndrome ; genetics ; Humans ; Mutation ; Schizophrenia ; etiology ; genetics

OBJECTIVETo explore the relationship between the microsatellite markers on chromosome 6 and schizophrenia by linkage disequilibrium analysis.

METHODSTwenty-eight microsatellite markers on chromosome 6 were evaluated in 115 affected-sib-pair and trios families. Linkage disequilibrium analysis was conducted according to diagnostic categories, Positive and Negative Syndrome Scale (PANSS) and other clinical data by XDT and MAPMAKER/SIBS software system.

RESULTSSignificant P value (P<0.005) was found in all the four diagnostic categories. Only the locus of D6S1960 showed positive P value (P<0.05) in all the subgroups divided by PANSS scale and the age of onset.

CONCLUSIONThe area around D6S1960 in short arm of chromosome 6 may contain susceptibility gene of schizophrenia.

Age of Onset ; Chromosomes, Human, Pair 6 ; Humans ; Linkage Disequilibrium ; Microsatellite Repeats ; genetics ; Schizophrenia ; genetics

Schizophrenia (MIM 181500) is a complex disorder affecting approximately 1% of the population worldwide. Epidemiologic evidences, together with recent linkage and association studies, have clearly demonstrated the high heritability of schizophrenia (up to 80%). Uncovering the genetic mechanism of schizophrenia has became one of the greatest challenges for both psychiatry and genetics. In recent years, remarkable advances in the genetics of this disorder has been achieved with the rapid growth of human genome information and experiment technologies. Several candidate genes within some of the best-supported linkage regions have been reported and, more importantly, replicated. Moreover, these genes present a significant connection in the signaling pathways implicated in the development of schizophrenia, especially NMDA receptor-mediated glutamate transmission. In this review, we summarize the recent advances in the genetics of schizophrenia, focusing particularly on linkage disequilibrium analysis and the latest understanding of the neurobiology of the disorder.
Acyltransferases ; genetics ; Carrier Proteins ; genetics ; Dysbindin ; Dystrophin-Associated Proteins ; Humans ; Membrane Proteins ; genetics ; Nerve Tissue Proteins ; genetics ; Neuregulin-1 ; Receptors, N-Methyl-D-Aspartate ; genetics ; Schizophrenia ; genetics

OBJECTIVES: Family, twin and adoption studies indicate that genetic factors play a crucial role in the etiology of schizophrenia. However, mode of inheritance of schizophrenia is uncertain, and genes for schizophrenia have not yet been identified despite extensive studies due to the complexity of the genetics of schizophrenia. Currently, 5HT2A receptor gene has attracted considerable interest as a susceptibility gene of schizoph,enia since the 5HT2A receptor has been known as one of the major target sites of atypical neuroleptics. We conducted an association study of T102C polymorphism in the 5HT2a receptor gene in Korean schizophrenic patients using PCR-RFLF method. METHODS: Two hundered and fifty biologically unrelated schizoprenic patients meeting DSM-III-R criteria from Kangnam St. Mary's Hospital affiliated with Catholic University of Korea were recruited for our study. The patient group consisted of 123 male and 127 female subjects, aged 30.1+/-9.3years. The controls were volunteers for DNA library of Kangnam St. Mary's Hospital withoyt family history of psychiatric or neurologic illness. The control group consisted of 124 males and 112 females, aged 23.6+/-3.7year. Amplified genomic DNA was digested by MspI. The significance of genetic association of the polymorphism was estimated by the logisitc regression anlysis and ANOVA using SPSS 7.5. RESULT: The allele frequencies and the genotypic distribution 5HT2a receptor gene were not significantly different between the patient and control group. In addition the allele frequencies and the genotypes of 5HT2a receptor gene were not significantly associated with subtype of schizophrenia. However, negative symptom score according to genotype show significant differenence(F=3.828 df=2 P=0.023). CONCLUSION: It is suggested that even if the development and subtype of schizophrenia may not beassociated with T102C polymorphism of 5HT2A receptor in Korean population, T102C polymorphism may be associated with the severity of negative symptom.
Antipsychotic Agents ; DNA ; Female ; Gene Frequency ; Gene Library ; Genetics ; Genotype ; Humans ; Korea ; Male ; Schizophrenia* ; Volunteers ; Wills

PURPOSE: We investigated the association between the tryptohan hydroxylase 1 (TPH1) gene and aggression in schizophrenia in a Korean population. MATERIALS AND METHODS: The sample included 61 aggressive patients as well as 104 non-aggressive patients from psychiatric hospitals and 335 healthy volunteers in Korea. Blood samples were collected from all participants for TPH1 A218C genotyping. The patients were administered standard psychiatric interviews as well as a self-report questionnaire for anger-related traits. RESULTS: In the case-control phenotypic comparisons, there was no significant association between the aggressive patients and the TPH1 A218C polymorphism. There was no significant effect of the TPH1 genotype on the anger-related traits, or no significant interaction between the genotype and group (aggressive and non-aggressive patients). CONCLUSION: These findings suggest that TPH1 does not play a major role in aggressive behavior via anger in schizophrenic patients.
Adult ; Asian Continental Ancestry Group/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genotype ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Polymorphism, Genetic/*genetics ; Schizophrenia/*genetics ; Tryptophan Hydroxylase/*genetics ; Young Adult

OBJECTIVETo explore the molecular genetic relationship between chromosome 1 and quantitative trait loci for familial schizophrenia.

METHODSA series of assessment scales included positive and negative syndrome scale (PANSS), global assessment of functional scale (GAFS), premorbid schizoid and schizotypal traits scale (PSST), premorbid social adjustment scale (PSA) were applied to quantify the phenotypes of schizophrenia. Non-parametric linkage analysis of quantitative traits was conducted in 32 multiplex pedigrees with schizophrenia by using 29 microsatellite makers on chromosome 1.

RESULTSHaseman-Elston quantitative trait analysis detected a maximum Traditional H-E Lods of 1.73 and a maximum EH H-E Lods of 1.65 of negative symptoms (PANSS-N ) at 147.64 cM, which was overlapped to the positive region of 1q21-23 in qualitative linkage analysis.

CONCLUSIONThe results suggest there might be an independent quantitative trait locus of negative symptoms on 1q21-23 for familial schizophrenia.

Chromosomes, Human, Pair 1 ; genetics ; Family Health ; Genetic Linkage ; Humans ; Lod Score ; Microsatellite Repeats ; Quantitative Trait, Heritable ; Schizophrenia ; genetics

OBJECTIVETo reconfirm the association of KPNB3 with schizophrenia in Chinese population.

METHODSTwo single nucleotide polymorphisms (SNPs), rs2588014 and rs626716 at the KPNB3 locus, were genotyped in 304 Chinese Han family trios consisting of fathers, mothers, and affected offsprings with schizophrenia. These 2 SNPs were detected by PCR-based restriction fragment length polymorphism (RFLP) analysis. The Hardy-Weinberg equilibrium for genotypic distributions was estimated by the goodness-of-fit test. The UNPHASED program was used to perform transmission disequilibrium test (TDT), haplotype analysis, and pair-wise measure of linkage disequilibrium (LD) between these 2 SNPs.

RESULTSThe genotypic distributions of both rs2588014 and rs626716 were in the Hardy-Weinberg equilibrium (P > 0.05). The TDT revealed allelic association with rs626716 (chi2 = 9.31, P = 0.0023) but not with rs2588014 (chi2 = 3.44, P = 0.064). The global P-value was 0.0099 for 100 permutations. The haplotype analysis also showed a disease association (chi2 = 25.97, df = 3, P = 0.0000097).

CONCLUSIONThe present study provides further evidence in support of the KPNB3 association with schizophrenia in Chinese population.

Adult ; China ; epidemiology ; Female ; Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Polymorphism, Single Nucleotide ; Schizophrenia ; epidemiology ; genetics ; beta Karyopherins ; genetics

OBJECTIVETo investigate the genetic association between schizophrenia and the polymorphism of GABA(A) receptor β2 subunit (GABRB2) gene.

METHODSA population association analysis was performed of 5 single nucleotide polymorphisms (SNPs) in the proximal promoter of GABRB2 gene by PCR and sequencing of the genomic DNA in a cohort of 172 schizophrenics and 167 controls of Chinese Han nationality.

RESULTSOne out of the 5 SNPs, namely rs3811996, was found to be significantly associated with schizophrenia especially in the male cohorts, where the heterozygous genotypes (A/G) and minor allele G displayed lower frequencies in case group than in the controls.

CONCLUSIONWe found a new risk, SNP rs3811996, for paranoia schizophrenia, which further supports the importance of genetic variations of GABRB2 in the etiology of schizophrenia.

Alleles ; Case-Control Studies ; Ethnic Groups ; Heterozygote ; Humans ; Male ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Receptors, GABA-A ; genetics ; Schizophrenia ; genetics