A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1-3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European-and in African-American individuals. A 5 0 CB1/Cnr1 'TAG' haplotype displays significant allelic frequency differences between substance abusers and controls in European-American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/ Cnr1 genomic variation thus appears to play roles in human addiction vulnerability. Molecular Psychiatry (2004) 9, 916-931.

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NMDA receptor dysfunction may be involved in the pathophysiology of schizophrenia. Based on this hypothesis, we screened 48 Japanese patients with schizophrenia for mutations in the coding region of the NMDAR2B subunit gene (GRIN2B). An association study between the identified DNA sequence variants and schizophrenia was performed in 268 Japanese patients with schizophrenia and 337 Japanese control subjects. Eight single nucleotide polymorphisms were detected, all of which were synonymous. The association sample showed statistically significant excesses of homozygosity for the polymorphisms in the 3' region of the last exon in the patients with schizophrenia (P = 0.004) and higher frequency of the G allele of the 366C/G polymorphism (corrected P = 0.04) in the patients than in the controls. Although we did not detect NMDAR2B protein variants, our findings support the possibility that the GRIN2B gene or a locus in linkage disequilibrium with it may confer susceptibility to schizophrenia. Replication studies in independent samples are warranted. Molecular Psychiatry (2001) 6, 211-216.The glutamate dysfunction hypothesis is one of the main explanatory hypotheses for the pathophysiology of schizophrenia. It originated from the observation that phencyclidine (PCP) intoxication closely mimics schizophrenia. 1 At serum levels that produce schizophrenic symptoms, PCP acts as a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptors. 2 Ketamine and MK-801, two additional noncompetitive antagonists of NMDA receptors, also produce schizophrenic symptoms and exacerbate symptoms in patients with schizophrenia. [3][4][5] NMDA receptors, together with alpha-amino-3-hydroxy-5-methyl-4-isozaxole propionic acid (AMPA) and kainate receptors, comprise the known ionotropic glutamate receptors. 6 Functional NMDA receptors are composed of a common NMDAR1 subunit and one of four NMDAR2 subunits (NMDAR2A-NMDAR2D) combined in an undetermined ratio to make the heteromeric receptor complex. 7,8 Knockout mice lacking each of the known NMDA receptor subunits have been generated. 9-15 Mice lacking NMDAR1 or NMDAR2B protein die perinatally, 9,10,14 knockdown mice expressing only 5% of normal levels of the essential NMDAR1 subunit survive to adulthood but display behavioral abnormalities including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior. 16 NMDAR2B mRNA is found throughout the entire embryonic brain in mice, but its expression becomes restricted to the forebrain postnatally. 17,18 There is a high degree of regional specialization with respect to specific NMDA receptors within the basal ganglia, and NMDAR2B is abundant in the striatum. 19 NMDAR2B mRNA expression is regulated by cortico-striata...

The Japanese Schizophrenia Sib-Pair Linkage Group (JSSLG) is a multisite collaborative study group that was organized to create a national resource for affected sib pair (ASP) studies of schizophrenia in Japan. We used a high-density single-nucleotide-polymorphism (SNP) genotyping assay, the Illumina BeadArray linkage mapping panel (version 4) comprising 5,861 SNPs, to perform a genomewide linkage analysis of JSSLG samples comprising 236 Japanese families with 268 nonindependent ASPs with schizophrenia. All subjects were Japanese. Among these families, 122 families comprised the same subjects analyzed with short tandem repeat markers. All the probands and their siblings, with the exception of seven siblings with schizoaffective disorder, had schizophrenia. After excluding SNPs with high linkage disequilibrium, we found significant evidence of linkage of schizophrenia to chromosome 1p21.2-1p13.2 (LOD=3.39) and suggestive evidence of linkage to 14q11.2 (LOD=2.87), 14q11.2-q13.2 (LOD=2.33), and 20p12.1-p11.2 (LOD=2.33). Although linkage to these regions has received little attention, these regions are included in or partially overlap the 10 regions reported by Lewis et al. that passed the two aggregate criteria of a meta-analysis. Results of the present study--which, to our knowledge, is the first genomewide analysis of schizophrenia in ASPs of a single Asian ethnicity that is comparable to the analyses done of ASPs of European descent--indicate the existence of schizophrenia susceptibility loci that are common to different ethnic groups but that likely have different ethnicity-specific effects.