| 1 | Mol. Psychiatry 2000 Sep 5: 495-501 |
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| PMID | 11032382 |
| Title | Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. |
| Abstract | The sequence and genomic organization of the human Golfalpha (GNAL) gene were determined. The human GNAL gene was found to contain 12 coding exons, and it spans over 80 kb on chromosome 18p11. 5' RACE analysis suggested an additional transcription initiation start site. Sequence analysis of the putative promoter region revealed conserved binding sites for several transcription factors. Sequence analysis of the 3'-untranslated region revealed the presence of two Alu sequences and two polyadenylation siGNALs. 3' RACE analysis confirmed the functionality of the most downstream poly-a siGNAL. The human GNAL was found to be expressed as a single transcript of about 5.9 kb in the brain. One highly informative dinucleotide repeat was found in intron 5. Additionally, a processed pseudogene for asparagine synthetase was found about 6 kb upstream of the GNAL gene. Knowledge of the sequence and structure of the human GNAL gene provides essential information for further analysis of the GNAL locus at chromosome 18p11 which has been linked to bipolar disorder and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 2 | Mol. Psychiatry 2001 Mar 6: 202-10 |
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| PMID | 11317223 |
| Title | Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. |
| Abstract | In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 3 | Mol. Psychiatry 2001 Mar 6: 202-10 |
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| PMID | 11317223 |
| Title | Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. |
| Abstract | In our search for candidate genes for affective disorder on the short arm of chromosome 18, we cloned IMPA2, a previously unreported myo-inositol monophosphatase gene, that maps to 18p11.2. We determined its genomic structure and detected three new single nucleotide polymorphisms (SNPs). In the present study, we screened the gene further to search for additional polymorphisms in Japanese samples and identified seven other SNPs, including a novel missense mutation. These polymorphisms clustered into three regions of the gene. Three relatively informative SNPs, 58G>A, IVS1--15G>A and 800C>T from clusters 1, 2 and 3, respectively, were selected for association tests using a case-control design. The Japanese cohort included 302 schizophrenics, 205 patients with affective disorder and 308 controls. Genotyping was done either by melting curve analysis on the LightCycler or by sequencing. All three SNPs showed significant genotypic association (nominal P = 0.031--0.0001) with schizophrenia, but not with affective disorder. These findings increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity to IMPA2. Our findings suggest that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 4 | Clin Invest Med 2003 Dec 26: 285-302 |
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| PMID | 14690303 |
| Title | Genetic analysis of psychiatric disorders associated with human chromosome 18. |
| Abstract | Current models on the etiology of psychiatric disorders support the idea of a biologic cause as well as interactions of biologic systems with the environment. The elucidation of the genetic etiology is of paramount importance to understand the cause of psychiatric disorders. Human chromosome 18 was identified as one of the first chromosomes to be aberrant in psychiatric patients and has subsequently served as a model to identify the molecular cause. In this article I review a multitude of methodologies that can be used in determining the genetic basis of schizophrenia, affective disorder and autism associated with human chromosome 18. These strategies include the use of chromosome aberrations, linkage and association studies, mouse-human comparative genomics, mutation analysis on candidate genes, trinucleotide repeat expansion studies, search for genes demonstrating parental effects and bioinformatics. Current data from the use of these methods are cited from the literature. Linkage and association studies have suggested at least 2 candidate loci on the short and long arms of chromosome 18 for each of these psychiatric disorders. Some loci are supported by the mapping of chromosome aberrations from psychiatric patients. Mutation analyses of psychiatric patients with 4 candidate genes (NEDD4L, IMPA2, PACAP and GNAL) mapping within these loci have been unsuccessful, although an association was found with the IMPA2 gene in patients with schizophrenia. With these methods and findings, our understanding of the cause of psychiatric disorders associated with human chromosome 18 has improved and will advance, especially with emerging data from the human and rodent genome projects. |
| SCZ Keywords | schizophrenia, schizophrenics |
| 5 | Mol. Psychiatry 2005 Nov 10: 1017-25 |
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| PMID | 16044173 |
| Title | Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. |
| Abstract | Genetic studies implicating the region of human chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia have observed parent-of-origin effects that may be explained by genomic imprinting. We have identified a transcriptional variant of the GNAL gene in this region, employing an alternative first exon that is 5' to the originally identified start site. This alternative GNAL transcript encodes a longer functional variant of the stimulatory G-protein alpha subunit, Golf. The isoforms of Golf display different expression patterns in the CNS and functionally couple to the dopamine D1 receptor when heterologously expressed in Sf9 cells. In addition, there are CpG islands in the vicinity of both first exons that are differentially methylated, a hallmark of genomic imprinting. These results suggest that GNAL, and possibly other genes in the region, is subject to epigenetic regulation and strengthen the case for a susceptibility gene in this region. |
| SCZ Keywords | schizophrenia, schizophrenics |