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.
", especially a 30cM region around 8p21.1-22, has been implicated as a locus harboring one or more schizophrenia genes by several linkage studies (Blouin et al 1998; Brzustowicz et al 1999; Gurling et al 2001; Kendler et al 1996; Levinson et al 1996; Liu et al 2005; Pulver et al 1995; Stefansson et al 2002). As with all other putative schizophrenia loci, there have also been equivocal and negative findings (DeLisi et al 2000; Kaufmann et al 1998; Kunugi et al 1996; Shaw et al 1998; Sklar et al 2004; Williams et al 2003a); importantly, however, the two meta-analyses of schizophrenia genome scans identified 8p as a disease locus with a high probability. Badner and Gershon (2002) reported an overall p value of Ͻ 2 ϫ 10 Ϫ4 , whereas Lewis et al (2003), with a more conservative approach, found p Ͻ .05 for both permutation tests used. "
[Show abstract][Hide abstract] ABSTRACT: Neuregulin 1 (NRG1) is a leading schizophrenia susceptibility gene. The NRG1 locus on chromosome 8p shows linkage to the disorder, and genetic association has been found between schizophrenia and various non-coding polymorphisms and haplotypes, especially at the 5' end of the NRG1 gene, in many but not all case-control and family studies. NRG1 is a pleiotropic growth factor, important in nervous system development and functioning; roles include the modulation of neuronal migration, synaptogenesis, gliogenesis, neuron-glia communication, myelination, and neurotransmission. Understanding the neurobiology of NRG1 and its involvement in schizophrenia is challenged by the complexity of the gene, which gives rise to multiple functionally distinct isoforms, including six "types" of NRG1 defined by 5' exon usage. Type IV and type I NRG1 may be particularly relevant to schizophrenia, with initial data showing altered expression of these isoforms in the disorder or in association with NRG1 risk alleles. We review the structure and functions of NRG1, consider the evidence for and against it being a schizophrenia susceptibility gene, and discuss mechanisms that might underlie the contribution of NRG1 to disease pathophysiology.
"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. "
[Show abstract][Hide abstract] 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 · 3.42 Impact Factor
"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 "
[Show abstract][Hide abstract] 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 · 10.93 Impact Factor
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