Article

A linkage study of schizophrenia with DNA markers from chromosome 8p21-p22 in 25 multiplex families

Teikyo University, Edo, Tōkyō, Japan
Schizophrenia Research (Impact Factor: 4.43). 11/1996; 22(1):61-8. DOI: 10.1016/0920-9964(96)00048-5
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ABSTRACT Two recent genome-wide searches for linkage (Lasseter et al., 1994; Moises et al., 1995) suggested that a susceptibility gene for schizophrenia might be located at chromosome 8p21-p22. We attempted to replicate these findings by performing a linkage study of schizophrenia with four DNA markers from this region using 25 multiply affected families. Neither the lod score method nor non-prametric extended sib-pair analysis yielded any evidence for linkage, even under the assumption of locus heterogeneity. We conclude that there is unlikely to be a major gene in the 8p21-p22 region which confers susceptibility to schizophrenia in our set of families. However we cannot exclude the possibility of a major gene present in other families, or of a susceptibility gene with a moderate but widespread effect which we cannot detect.

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    • "Recently, another genome-wide scan of an Icelandic sample also revealed a multipoint LOD score of 3.48 at D8S278, and further fine-mapping of the 8p locus identified neuregulin 1 gene (NRG1) as a positional candidate gene by haplotype association study [Stefansson et al., 2002]. Other studies of 8p22-21 have either offered less significant statistical support [Kaufmann et al., 1998; Shaw et al., 1998] or have been negative [Kunugi et al., 1996; DeLisi et al., 2000]. The studies showing significant or suggestive linkage to chromosome 8p22-21 were all applied to Caucasian samples. "
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    ABSTRACT: Positive linkage of schizophrenia to chromosome 8p22-21 loci had been reported in the Caucasian samples. This study was designed to replicate this finding by using eleven microsatellite markers on chromosome 8p22-21 in 52 Taiwanese schizophrenic families with at least two affected siblings. Two phenotype models (narrow: DSM-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other non-affective psychotic disorders) were used to define the disease phenotype. Maximum non-parametric linkage scores (NPL score) of 2.45 (P = 0.008) and 1.89 (P = 0.02) were obtained for the marker D8S1222 under the broad and narrow models, respectively. Positive linkage was found across about a 4-cM region. The marker D8S1222 was about 400 kbp distal to the exon 1 of glial growth factor 2 (GGF2), an isoform of Neuregulin 1 gene (NRG1), which has been highly suggested to be a candidate gene for schizophrenia. The results provide suggestive linkage evidence of schizophrenia to loci near NRG1 on chromosome 8p21 in an ethnically distinct Taiwanese sample. Further exploration of the candidate gene and nearby chromosome regions is warranted.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2005; 134B(1):79-83. DOI:10.1002/ajmg.b.20161
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    • "Given this, it is not surprising that despite the slightly different genetic models used by different investigators for their parametric-linkage studies, the same small regions of chromosomes 8 and 13 have been implicated in schizophrenia susceptibility, by a number of groups. It is also clear, however, that not all samples have produced suggestive or significant evidence of linkage to these regions (Coon et al. 1994; Kunugi et al. 1996; Barden and Morissette 1998; Faraone et al. 1998; Levinson et al. 1998; Wildenauer and Schwab 1998 "
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    ABSTRACT: Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.
    The American Journal of Human Genetics 11/1999; 65(4):1096-103. DOI:10.1086/302579
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    • "The aforementioned international collaborative replication study likewise found suggestive evidence for linkage in the vicinity of D8S133 [Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6, and 8, 1996] and the aforementioned international 2- stage linkage collaboration conducted by Moises et al. [1995] found suggestive evidence for linkage at D8S298 {23.350} and D8S260 {65.900} in the first stage scan, although this was not supported in the second stage of their design. A smaller study, comprising 25 multiplex pedigrees, likewise could not support linkage in this region [Kunugi et al., 1996]. It it worth mentioning that this region harbors a QTL locus accounting for 38% of the variance associated with harm avoidance [Cloninger et al., 1998], a quantitative behavioral phenotype that serves as a risk factor for many forms of psychopathology, including psychosis [Cloninger et al., 1994]. "
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    ABSTRACT: The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.
    American Journal of Medical Genetics 08/1998; 81(4):282-9. DOI:10.1002/(SICI)1096-8628(19980710)81:43.0.CO;2-W
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