A balanced (1;11)(q421;q143) translocation segregates with schizophrenia and related psychiatric disorders in a large Scottish family (maximum LOD = 60) We hypothesize that the translocation is the causative event and that it directly disrupts gene function We previously reported a dearth of genes in the breakpoint region of chromosome 11 and it is therefore unlikely that the expression of any genes on this chromosome has been affected by the translocation By contrast, the corresponding region on chromosome 1 is gene dense and, not one, but two novel genes are directly disrupted by the translocation These genes have been provisionally named Disrupted-In-Schizophrenia 1 and 2 (DISC1 and DISC2) DISC1 encodes a large protein with no significant sequence homology to other known proteins It is predicted to consist of a globular N-terminal domain(s) and helical C-terminal domain which has the potential to form a coiled-coil by interaction with another, as yet, unidentified protein(s) Similar structures are thought to be present in a variety of unrelated proteins that are known to function in the nervous system The putative structure of the protein encoded by DISC1 is therefore compatible with a role in the nervous system DISC2 apparently specifies a non-coding RNA molecule that is antisense to DISC1, an arrangement that has been observed at other loci where it is thought that the antisense RNA is involved in regulating expression of the sense gene Altogether, these observations indicate that DISC1 and DISC2 should be considered formal candidate genes for susceptibility to psychiatric illness

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Disruption of two novel genes by a translocation co-segregating with schizophrenia

AKT-GSK3beta signaling is a target of lithium and as such has been implicated in the pathogenesis of mood disorders. Here, we provide evidence that this signaling pathway also has a role in schizophrenia. Specifically, we present convergent evidence for a decrease in AKT1 protein levels and levels of phosphorylation of GSK3beta at Ser9 in the peripheral lymphocytes and brains of individuals with schizophrenia; a significant association between schizophrenia and an AKT1 haplotype associated with lower AKT1 protein levels; and a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine, conferred by AKT1 deficiency. Our findings support the proposal that alterations in AKT1-GSK3beta signaling contribute to schizophrenia pathogenesis and identify AKT1 as a potential schizophrenia susceptibility gene. Consistent with this proposal, we also show that haloperidol induces a stepwise increase in regulatory phosphorylation of AKT1 in the brains of treated mice that could compensate for an impaired function of this signaling pathway in schizophrenia.

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Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia.

Badner and Gershon (2001) presented a technique of meta-analysis of linkage data that could be applied to published genome scans. It combines the reported P-values of individual studies, after correcting each value for the size of the region containing a minimum P-value. Simulations demonstrated that the type I error rate was at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied. Power to detect linkage was at least as high as the power of pooling the data from all the studies. We applied this method to all the published genome scans for bipolar disorder and schizophrenia. We found the strongest evidence for susceptibility loci on 13q (P < 6 x 10(-6)) and 22q (P < 1 x 10(-5)) for bipolar disorder, and on 8p (P < 2 x 10(-4)), 13q (P < 7 x 10(-5)), and 22q (P < 9 x 10(-5)) for schizophrenia.

Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia

A family with a (1;11)(q42;q14.3) translocation significantly linked to a clinical phenotype that includes schizophrenia and affective disorders is described. This translocation generates a LOD score of 3.6 when the disease phenotype is restricted to schizophrenia, of 4.5 when the disease phenotype is restricted to affective disorders, of 7.1 when relatives with recurrent major depression, with bipolar disorder, or with schizophrenia are all classed as affected. This evidence for linkage is among the strongest reported for a psychiatric disorder. Family members showed no distinctive features by which the psychiatric phenotype could be distinguished from unrelated cases of either schizophrenia or affective disorders, and no physical, neurological, or dysmorphic conditions co-occurred with psychiatric symptoms. Translocation carriers and noncarriers had the same mean intelligence quotient. Translocation carriers were similar to subjects with schizophrenia and different from noncarriers and controls, in showing a significant reduction in the amplitude of the P300 event-related potential (ERP). Furthermore, P300 amplitude reduction and latency prolongation were measured in some carriers of the translocation who had no psychiatric symptoms—a pattern found in other families with multiple members with schizophrenia, in which amplitude of and latency of P300 appear to be trait markers of risk. The results of karyotypic, clinical, and ERP investigations of this family suggest that the recently described genes DISC1 and DISC2, which are directly disrupted by the breakpoint on chromosome 1, may have a role in the development of a disease phenotype that includes schizophrenia as well as unipolar and bipolar affective disorders.

/pdf/schizophrenia-and-affective-disorders-cosegregation-with-a-4icc78d321.pdf

Schizophrenia and Affective Disorders—Cosegregation with a Translocation at Chromosome 1q42 That Directly Disrupts Brain-Expressed Genes: Clinical and P300 Findings in a Family

Bipolar disorder (BP) is a severe psychiatric disease, with a strong genetic component, that affects 1% of the population worldwide and is characterized by recurrent episodes of mania and depression Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of mood disorders, and the aim of the present study was to test for the presence of linkage disequilibrium between two polymorphisms in the BDNF gene and BP in 283 nuclear families Family-based association test (FBAT) results for the dinucleotide repeat (GT)N polymorphism at position −1040 bp showed that allele A3 was preferentially transmitted to the affected individuals (Z=2035 and P=042) FBAT results for the val66met SNP showed a significant association for allele G (Z=3415 and P=00064) Transmission/disequilibrium test (TDT) haplotype analysis showed a significant result for the 3-G allele combination (P=000394), suggesting that a DNA variant in the vicinity of the BDNF locus confers susceptibility to BP Given that there is no direct evidence that either of the polymorphisms we examined alters function, it is unlikely that the actual risk-conferring allele is from these two sites Rather, the causative site is likely nearby and in linkage disequilibrium with the 3-G haplotype that we have identified

The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study.

Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component. To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on ≈396 individuals from 22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0.000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder, and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2.67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions, 7q31 (lod = 2.08; P = 0.00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the overlap of susceptibility regions for bipolar disorder and schizophrenia.

Jin Zeng

Papers

A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2