Linkage disequlibrium in the DTNBP1 (dysbindin) gene region and on chromosome 1p36 among psychotic patients from a genetic isolate in Israel: Findings from identity by descent haplotype sharing analysis

Abstract

Several genes have been reported recently to be associated with schizophrenia and bipolar disorder. Because of the complexity of the inheritance of these disorders, there is an urgent need to replicate these findings and to search for additional candidate genes. The study of genetic isolates is a powerful technique that may overcome some of the obstacles caused by genetic heterogeneity and ambiguity of phenotype definition. Identity by descent (IBD) haplotype sharing analysis in these populations may be used to detect mutations within shared haplotypes in smaller samples of affected individuals. In this study, we used IBD haplotype sharing analysis to replicate positive linkage and association findings in psychotic disorders, and to identify other regions of interest. Fifty-two patients with major psychiatric disorders from a genetically isolated village in Israel were studied. By studying eight Y chromosome markers, we were able to confirm the oral tradition of members of this isolate regarding a common paternal origin. Three hundred fifty nine microsatellite markers on 9 candidate chromosomes were genotyped, and haplotypes were reconstructed using information from family members. Two highly significant (P < 0.0001) peaks of haplotype sharing were found. One was for psychotic patients with any diagnosis at the location of dysbindin, a gene previously associated with schizophrenia. The other peak was for patients with schizophrenia on chromosome 1p36. Thus, this study both replicates an earlier finding and points to a novel region of interest, which might be unique to this population.

A genome‐wide scan for schizophrenia and psychosis susceptibility loci in families of Mexican and Central American ancestry

“…With the same phenotype (DSM-IV psychosis) in our study, we observe a multipoint NPL score of 2.83 (empirical P ¼ .00061) at this location (16 cM from the pter) and observe a peak multipoint NPL of 3.42 (empirical P ¼ 0.00003) at a location 21 cM centromeric to that locus. Since only two previous studies [Kohn et al, 2004;Craddock et al, 2005] had reported weak (non-significant) linkage to this region, the present study provides the first replication of the report by Abecasis et al [2004] of a locus for psychosis at this site. The present study also provided evidence for a gene related to schizophrenia and psychosis in the chromosome 5q35 region.…”

Relationship Between a High-Risk Haplotype in the DTNBP1 (Dysbindin) Gene and Clinical Features of Schizophrenia

“…Recently, several genes demonstrating strong evidence of association with schizophrenia have been identified (6,7). It has yet to be established whether these are susceptibility genes for schizophrenia in all populations, but association with both dystrobrevin binding protein 1 (DTNBP1), which codes for dysbindin (8), and neuregulin 1 (9) has been subsequently replicated in other samples (10)(11)(12)(13)(14)(15)(16)(17)(18). The involvement of dysbindin in the pathophysiology of schizophrenia is supported by recent findings that its expression is reduced in both the prefrontal cortex (19) and presynaptic hippocampal sites (20) in schizophrenia.…”

Association study of DTNBP1 with schizophrenia in a US sample

“…At least 40 family-based or population-based association studies have attempted to replicate this initial finding (summarized in Table 1), although not necessarily in the strict sense of repeating the design and methods of the initial study. One linkage study in an Israeli isolate directly located a risk region for major psychiatric disorders at the DTNBP1 locus (Kohn et al 2004). At least twenty-two association studies supported the associations between DTNBP1 and schizophrenia in different populations, but seven did not.…”