Disrupted-In-Schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (⌬3), exons 7 and 8 (⌬7⌬8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms ⌬7⌬8, Esv1, and ⌬3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of ⌬3 and ⌬7⌬8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1⌬7⌬8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.alternative splicing ͉ genetic ͉ hippocampus ͉ psychiatric illness S chizophrenia is a common mental disorder with a lifetime prevalence of Ϸ 1% (1). It has been assumed, on the basis of evidence from twin, family, and adoption studies, that genetic factors play a strong etiologic role in schizophrenia (2, 3). The genetic predisposition is likely to be determined by a complex network of interactions between genes and environmental risk factors (4).The Disrupted-In-Schizophrenia-1 (DISC1) gene was identified as a potential susceptibility gene for mental disorders based on studies of a chromosomal translocation found in a large Scottish family that had a high frequency of schizophrenia and other psychiatric disorders, including bipolar disorder and major depression (5-7). Although the translocation identified in the Scottish family has not been observed in any other families, independent support for involvement of DISC1 in the etiology of mental illness has come from a number of genetic linkage and association studies in diverse populations (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the specific SNPs, alleles, and haplotypes have varied across these studies, raising issues of allelic and populations heterogeneity, the overall evidence implicates DISC1 as a promising candidate susceptibility gene for schizophrenia. However, the mechanism by which DISC1 contributes to the pathophysiology of schizophrenia remains unknown. Although reduced expression of DISC1 mRNA was found in lymphoblastoid cell lines of family members with the translocation (26) and in bipolar disorder patients with a putative risk-associated haplotype (27), no changes were detected in the brain tissue of unre...

To examine the cannabinoid hypothesis for pathogenesis of schizophrenia, we examined two kinds of polymorphisms of the CNR1 gene, which encodes human CB1 receptor, a subclass of central cannabinoid receptors, in schizophrenics and age-matched controls in the Japanese population. Allelic and genotypic distributions of polymorphism 1359G/A at codon 453 in the coding region and AAT triplet repeats in the 3Ј flanking region in the Japanese population were quite different from those in Caucasians. Although the polymorphism 1359G/A was not associated with schizophrenia, the triplet repeat polymorphism of the CNR1 gene was significantly associated with schizophrenia, especially the hebephrenic subtype (P = 0.0028). Hebephrenic schizophrenia showed significantly increased rate of the 9 repeat allele (P = 0.032, OR = 2.30, 95% CI (1.91-2.69)), and decreased rate of the 17 repeat allele (P = 0.011, OR = 0.208, 95% CI (0.098-0.439)). The present findings indicated that certain alleles or genotypes of the CNR1 gene may confer a susceptibility of schizophrenia, especially of the hebephrenic type. Molecular Psychiatry (2002Psychiatry ( ) 7, 515-518. doi:10.1038 The cannabinoid hypothesis for the pathogenesis of schizophrenia is supposed to be based on the clinical facts that abuse of cannabis could precipitate the psychotic state, with hallucinations and delusions resembling schizophrenia 1-4 and worsen positive symptoms of schizophrenia, 5,6 even under regular medication of antipsychotics. 7 Cannabinoid consumption could result in poor outcome and liability to relapse for schizophrenics. [8][9][10] In addition, heavy cannabis users may develop an amotivational syndrome, reminiscent of some of the negative symptoms of schizophrenia. 11 A Swedish cohort study showed that cannabis use before 18 years of age raises the incidence rate of schizophrenia six-fold. 12 Another study showed that administration of delta-9-hydrocannabinol to normal volunteers induced cognitive impairment of three dimensions resembling closely that of schizophrenic patients. 13 The hallucinogenic action of cannabis and marijuana mediated the central cannabinoid receptor, G protein-coupled receptor CB1, which was discovered in 1988. 14 CB1 receptors were expressed abundantly throughout the brain, especially in substantia nigra, globus pallidus, hippocampus and cerebellum. 15,16 CB1 receptors are encoded by the CNR1 gene (MIM114610), which was cloned by Matsuda et al in 1992. 17 CB1 is located at 6q14-q15, which was included in a schizophrenia susceptibility locus, 6q13-q26, revealed by Cao et al 18 using two independent series of pedigrees, which was designated by Schizophrenia 5 (SCZ5, OMIM 603175). Recently, two polymorphisms, AAT repeats microsatellite in the 3Ј flanking region and 1359 G/A polymorphism at codon 453 in the coding exon of the CNR1 gene, were reported. 19,20 To examine the cannabinoid hypothesis for schizophrenia, we examined these two polymorphisms in the CNR1 gene of schizophrenia in the Japanese population.Genotypic distribution and a...

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10−5 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10−7 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10−9) and rs3781834 (P = 1.04×10−8). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10−5) and rs744373 near BIN1 (P = 1.39×10−4). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

Susceptibility to drug dependence and drug-induced psychoses is influenced not only by the pharmacological effects of the drug but also by the genetic factors of the individual. To clarify the latter, we investigated the association between methamphetamine (METH) dependence/psychosis and the hDAT1 gene (SLC6A3) encoding the dopamine transporter, which is the primary site of METH activity in the brain. Four exonic polymorphisms of the hDAT1 gene, 242C/T (exon 2), 1342A/G (exon 9), 2319G/A (3 0 UTR), and VNTR (3 0 UTR) were examined. Although there was no significant difference in genotypic and allelic distribution of the four polymorphisms between all METH dependence/psychosis patients (N ¼ 124) and controls (N ¼ 160), the patients with METH psychosis lasting for 1 month or more after discontinuance of METH consumption showed a significant excess of nine-or fewer repeat alleles of the VNTR in 3 0 UTR of the hDAT1 gene (P ¼ 0.0054, OR ¼ 4.24, 95% CI ¼ 2. 46-7.31). The present study demonstrated that the presence of nineor fewer repeat alleles of hDAT1 is a strong risk factor for a worse prognosis of METH psychosis.

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Recent progress in genotyping technology and the development of public databases has enabled large-scale genome-wide association tests with diseases. We performed a two-stage genome-wide association study (GWAS) of bipolar disorder (BD) in Japanese cohorts. First we used Affymetrix 100K GeneChip arrays in the analysis of 107 cases with bipolar I disorder and 107 controls, and selected markers that were nominally significant (P < 0.01) in at least one of the three models (1,577 markers in total). In the follow-up stage, we analyzed these markers using an Illumina platform (1,526 markers; 51 markers were not designable for the platform) and an independent sample set, which consisted of 395 cases (bipolar I + II) and 409 controls. We also assessed the population stratification of current samples using principal components analysis. After the two-stage analysis, 89 markers remained nominally significant (allelic P < 0.05) with the same allele being consistently over-represented in both the first and the follow-up stages. However, none of these were significant after correction for multiple-testing by false discovery rates. Sample stratification was virtually negligible. Collectively, this is the first GWAS of BD in the Japanese population. But given the small sample size and the limited genomic coverage, these results should be taken as preliminary.

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