Cytogenetics and gene discovery in psychiatric disorders

Abstract

The disruption of genes by balanced translocations and other rare germline chromosomal abnormalities has played an important part in the discovery of many common Mendelian disorder genes, somatic oncogenes and tumour supressors. A search of published literature has identified 15 genes whose genomic sequences are directly disrupted by translocation breakpoints in individuals with neuropsychiatric illness. In these cases, it is reasonable to hypothesise that haploinsufficiency is a major factor contributing to illness. These findings suggest that the predicted polygenic nature of psychiatric illness may not represent the complete picture; genes of large individual effect appear to exist. Cytogenetic events may provide important insights into neurochemical pathways and cellular processes critical for the development of complex psychiatric phenotypes in the population at large.

Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder

“…1,2 A small proportion of these have been studied at the molecular level. 3 We have previously described a large Scottish family in which there is a highly significant co-segregation (LOD > 7) 4 between major mental illness and the presence of a balanced translocation between chromosomes 1 and 11. 5 The DISC1 gene is directly disrupted by the chromosome 1 breakpoint 6,7 and supportive evidence for its involvement with schizophrenia and bipolar disorder has come from linkage and case-control association studies on karyotypically normal populations [8][9][10][11][12] and from our recent demonstration of its activity-dependent interaction with the protein encoded by an independently disrupted gene, PDE4B.…”

A Hypothesis for How Chromosome 11 Translocations Cause Psychiatric Disorders

“…OTH the recent study (Baysal et al 2006) and a recent review (Pickard et al 2005) of the field clearly point out that the gene mutations causing major psychiatric schizophrenia and bipolar diseases have not been identified. Numerous chromosome regions were first identified by linkage analysis but all fell by the wayside as none of them has been definitively implicated in subsequent studies.…”

“…Therefore, the above quoted studies take a different tactic. Pickard et al (2005) searched literature for an association of chromosomal rearrangements with psychoses as a way to identify disease-conferring mutations. This search identified several rearrangements.…”

GWAS for psychiatric disease: is the framework built on a solid foundation?

“…Indeed, the accumulating evidence points strongly in this direction. [6][7][8] It is thus highly plausible that psychiatric disorders are inherited in similar manner to deafness, epilepsy or retinitis pigmentosa, which all can be caused by dominant or recessive mutations (model heterogeneity) in any one of a large number of genes (locus heterogeneity) and by alternative mutations (allelic heterogeneity) in the same gene, but which importantly point collectively to shared pathway biology. Each is individually rare in the population, specific to one lineal descent and maintained at a low level by the mutation-selection balance.…”

“…Copy-number variant studies are in turn simple extensions of the molecular cytogenetics approach, which through comparatively modest investment has nominated well replicated loci for psychiatric disease, such as the VCFS region on 22q11 and multiple biologically plausible genes, such as DISC1, PDE4B, GRIK4 and NPAS3. 6,7 Linkage studies have also been successful, for example, in identifying mutations in specific pedigrees that strongly predispose to autism. Although individually very rare, these discoveries have converged on a common biological pathway and thus provide invaluable insights into the pathogenic mechanisms.…”