DISC1 in Psychiatric Illness
Major psychiatric illnesses including bipolar disorder and schizophrenia can be highly debilitating and collectively have a lifetime incidence of approximately 1% in the general population. Twin and adoption studies have shown that there is a definite hereditary element to these disorders, estimated to be as high as 80% in some cases. Although there has been extensive research into these disorders from both pathological and genetic viewpoints, they are still poorly understood,and treatment of these disorders remains challenging. The Disrupted-in-Schizophrenia 1 (DISC1) locus on human chromosome 1 was identified as a consequence of its involvement in a balanced translocation (1;11)(q42.1;q14.3) segregating with major psychiatric illnesses in a single Scottish family. Since its discovery, the DISC1 gene has been the subject of numerous genetic and biological studies. However, due to original evidence showing that the chromosome 11 region disrupted by this translocation was largely absent of genes, the 11q14.3 region has not gained as much attention. Only recently has it been suggested that this region may also be of interest with a possible ability to create fusion proteins with DISC1. The DISC1 and 11q14.3 regions were examined by analysis of genome-wide scan data made available by the Genetic Association Information Network (GAIN) and other investigators (non-GAIN) through dbGap for association with bipolar disorder, schizophrenia and a combination of the two disorders. No single nucleotide polymorphisms (SNPs) within the DISC1 region were found to be significant (p-value<0.05) after correction for multiple testing in any of the datasets tested. There was evidence, however, supporting an association with schizophrenia for a group of SNPs in the 11q14.3 region in males with corrected p-valuesreaching 0.024. The molecular function of DISC1 was also assessed via a yeast two-hybrid screen using DISC1 as a bait. This analysis revealed 386 potential interacting partners of DISC1 of which only 13 had been reported previously. Gene set enrichment analysis of these data, combined with the published DISC1 interaction data and a further set of unpublished interactants, lead to an hypothesis of DISC1 having an additional function in the construction and maintenance of the primary cilium. Genetic interaction between a selection of SNPs in the genes that lead to this hypothesis and DISC1 by logistic regression analysis showed some evidence for interaction between DISC1 and TRAF3IP1, SYNE1 and FEZ2 at a genetic level (uncorrected significance only). The role of DISC1 in major psychiatric illness is not conclusive, with the most convincing evidence for genetic involvement to date coming from the translocation in the original Scottish family. DISC1 has suggested roles in brain development and there have been suggestive associations through linkage and association analyses for a role in psychiatric illness; however, the role of DISC1 as a strong candidate contributing to major psychiatric illness needs to be reconsidered as after extensive analyses the evidence remains anecdotal.
Advisor: Markie, David; Merriman, Tony
Degree Name: Doctor of Philosophy
Degree Discipline: Pathology/Biochemistry
Publisher: University of Otago
Keywords: DISC1; Psychiatric Illness; Schizophrenia; Bipolar Disorder; Association Analysis; Y2H
Research Type: Thesis