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Subtyping based on genetic linkage or association dataSeveral studies based on samples with well-characterized clinical phenotypes have examined associations between selected clinical features and previously established genetic linkage regions or putative candidate genes. Various approaches have been employed to interrogate genome-wide linkage or association data with a view to exploring pathways of disease expression. Thus, a potential 6p locus, associated with a quantitative trait assessing the severity of psychotic symptoms, was reported by Brzustowicz et al.175 Pulver et al.176 used diagnostic information to stratify 54 multiplex pedigrees by diagnostic phenotypes cosegregating in nonschizophrenic first-degree relatives of the probands and reported genome-wide significant linkage to 8p21 and suggestive linkage to 1p21 for schizophrenia spectrum personality disorders. Subsequent analyses of affected siblings from these families revealed that the linkage evidence for 8p21 was mainly contributed by a subgroup of 30 affected siblings sharing two alleles identity by descent in the 8p21 region and one allele at a locus on chromosome 14, suggesting an interaction effect. Phenotypically, this subgroup was characterized by a high prevalence of bizarre delusions, affective symptoms early in the course of illness, history of seizures, and attendance of special school.177 Using data from the Irish Study of High-Density Schizophrenia Families, Kendler et al.67 reported high levels of positive thought disorder, affective deterioration, and worse outcome in probands from families with evidence of linkage to 8p22–21, suggesting that a susceptibility gene in the region may be predisposing to a Kraepelinian, dementia praecox type of illness. Within the same cohort of families, family-based transmission disequilibrium tests produced suggestive evidence of association between affective symptoms and the His452Tyr polymorphism in the serotonin 2A receptor; between negative symptoms and the brain-derived neurotrophic factor (BDNF); and between negative symptoms and a high-risk haplotype in the dystrobrevin-binding protein 1 (dysbindin, DTNBP1) on 6p24–22.178, 179 Recently, an association between a six-locus haplotype in DTNBP1 and psychometrically assessed generalized cognitive deficit in schizophrenia patients was reported by Burdick et al.180 A special focus in the search for genetic subtypes of schizophrenia has been the Top of page Date: 2016-04-22; view: 762
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