ABSTRACT
Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.
Subject(s)
Genetic Predisposition to Disease , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Polymorphism, Single Nucleotide/genetics , Schizophrenia/genetics , Adult , Alleles , Animals , Antipsychotic Agents/administration & dosage , Behavior, Animal , Chi-Square Distribution , Disease Models, Animal , Female , Gene Frequency , Humans , Magnetic Resonance Imaging/methods , Male , Mice , Mice, Knockout , Middle Aged , Motor Activity/drug effects , Motor Activity/genetics , Neural Inhibition/drug effects , Neural Inhibition/genetics , Pituitary Adenylate Cyclase-Activating Polypeptide/deficiency , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Risperidone/administration & dosage , Schizophrenia/pathology , Schizophrenia/physiopathologyABSTRACT
We examined, for the first time, the possible association between schizophrenia and the anaplastic lymphoma kinase (ALK) gene which plays an important role in neurodevelopment. When two nonsynonymous polymorphisms (Arg1491Lys and Glu1529Asp) were examined, there were significant differences in genotype and allele distributions between patients and controls. Individuals homozygous for the minor allele (1491Lys-1529Asp) were more common in patients than in controls (p = 0.0064, odds ratio 2.4, 95% CI 1.3-4.6). These results suggest that genetic variations of the ALK gene might confer susceptibility to schizophrenia.
Subject(s)
Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Protein-Tyrosine Kinases/genetics , Schizophrenia/genetics , Alleles , Anaplastic Lymphoma Kinase , Female , Gene Frequency , Genotype , Humans , Japan/epidemiology , Male , Middle Aged , Polymerase Chain Reaction , Receptor Protein-Tyrosine KinasesABSTRACT
Previous studies have suggested that genetic variations in the brain-derived neurotrophic factor (BDNF) gene may be associated with several neuropsychiatric diseases including bipolar disorder. The present study examined a microsatellite polymorphism located approximately 1.0 kb upstream of the translation initiation site of the BDNF gene for novel sequence variations, association with bipolar disorder, and effects on transcriptional activity. Detailed sequencing analysis revealed that this polymorphism is not a simple dinucleotide repeat, but it is highly polymorphic with a complex structure containing three types of dinucleotide repeats, insertion/deletion, and nucleotide substitutions that gives rise to a total of 23 novel allelic variants. We obtained evidence supporting the association between this polymorphic region (designated as BDNF-linked complex polymorphic region (BDNF-LCPR)) and bipolar disorder. One of the major alleles ('A1' allele) was significantly more common in patients than in controls (odds ratio 2.8, 95% confidential interval 1.5-5.3, P=0.001). Furthermore, a luciferase reporter gene assay in rat primary cultured neurons suggests that this risk allele (A1) has a lower-transcription activity, compared to the other alleles. Our results suggest that the BDNF-LCPR is a functional variation that confers susceptibility to bipolar disorder and affects transcriptional activity of the BDNF gene.
Subject(s)
Bipolar Disorder/genetics , Brain-Derived Neurotrophic Factor/genetics , Dinucleotide Repeats , Polymorphism, Genetic , Transcription, Genetic/genetics , Adult , Alleles , Amino Acid Substitution , Animals , Base Sequence , Brain-Derived Neurotrophic Factor/physiology , Case-Control Studies , Cells, Cultured/metabolism , Female , Gene Frequency , Genes, Reporter , Genetic Predisposition to Disease , Humans , Japan , Linkage Disequilibrium , Male , Middle Aged , Molecular Sequence Data , Mutation, Missense , Neurons/metabolism , Point Mutation , Rats , Recombinant Fusion Proteins/biosynthesisABSTRACT
Two research groups have recently reported a significant association between schizophrenia and genetic variants of Frizzled-3 (FZD3) gene. We examined a possible association in a Japanese sample of schizophrenia, bipolar disorder, unipolar depression and controls with four single nucleotide polymorphisms (SNPs), tested in previous reports. We failed to find significant association in the four SNPs or haplotype analysis. The FZD3 gene might not play a role in conferring susceptibility to major psychosis in our sample.
