Linkage of schizophrenia with chromosome 1q loci in Taiwanese families

Hwu, Hai-Gwo; Liu, Chih-Min; Fann, Cathy S.J.; OuYang, W-C; Lee, S F-C

doi:10.1038/sj.mp.4001235

Cited by 123 publications

(83 citation statements)

References 51 publications

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“…PLXNA2 is located in the 1q32 region, a schizophrenia locus that was originally identified in a family-based linkage study 16 and has received support from several independent studies. [18][19][20] However, there have been several studies that did not confirm this locus. [21][22][23] This might be due to the inherent limitations of linkage studies, but could also be explained by the size and heterogeneity of samples used in the different studies.…”

Section: Discussionmentioning

confidence: 99%

“…We identified a gene on chromosome 1q32, plexin A2 (PLXNA2), as a candidate gene for schizophrenia. Several linkage studies previously reported schizophrenia susceptibility loci in the 1q22-42 region; [16][17][18][19][20] other studies, however, have been unable to reproduce these results. [21][22][23] The findings described here might be important for the elucidation of this controversial schizophrenia locus.…”

Section: Introductionmentioning

confidence: 92%

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Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genomewide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent casecontrol sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

et al. 2006

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“…Linkage 9,10 and association 11 of schizophrenia to 1q42 has been reported in Finnish populations, and linkage was also detected in a Taiwanese population. 12 Linkage to this region has also been reported in bipolar families. 13,14 Haplotype analysis with markers in DISC1 suggests an association with bipolar disorder, schizoaffective disorder, and schizophrenia in a collection of American families.…”

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confidence: 83%

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

et al. 2005

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In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3 0 end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders. Molecular Psychiatry (2005) 10, 758-764.

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“…9,10 Later, it was shown that a DISC1 intragenic microsatellite marker was linked to schizophrenia in a large Finnish family sample, 11 and the linkage was replicated with another DISC1 intragenic marker in an independent Finnish sample. 12 Observations of linkage to 1q42 to schizophrenia have since been observed in the Taiwanese, 13 and to bipolar disorder in a UK and Icelandic sample 14 ( Figure 1). The suggested functions of the TRAX and DISC genes also make them highly relevant for the etiology of psychotic disorders.…”

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confidence: 99%

A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia

et al. 2005

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We have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin-Associated Factor X (TRAX) and Disrupted in Schizophrenia 1 and 2 (DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation (1;11)(q42.1;q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/DISC would be associated with visual and/or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short-term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia.

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Linkage of schizophrenia with chromosome 1q loci in Taiwanese families

Cited by 123 publications

References 51 publications

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder

A haplotype within the DISC1 gene is associated with visual memory functions in families with a high density of schizophrenia

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