Investigation of DISC1, a candidate gene for susceptibility to schizophrenia and related major psychiatric illness

To investigate the genetic aetiology of schizophrenia and related psychiatric illness we are studying a large family in which a balanced chromosomal translocation co-segregates with major psychiatric disorders. This family generates a maximum LOD score of 7.1, indicating a likely involvement of the translocation in causing psychiatric illness. The translocation directly disrupts two genes, DISC1 & DISC2, that we are now investigating as candidate susceptibility genes using a combined genetic and functional approach. To assess the potential involvement of DISC1 in psychiatric illness in affected individuals unrelated to this family we are constructing a linkage disequilibrium map of the DISC1/DISC2 locus as an aid to genetic association studies. To begin identifying the role of DISC1, and the mechanism by which DISC1 disruption may cause psychiatric illness, we are investigating its subcellular localisation using immunofluorescence. In cultured human cell lines DISC1 is apparently organised along microtubules and is primarily associated with mitochondria. There have been several reports of mitochondrial abnormalities in post-mortem brain of individuals diagnosed with schizophrenia and related psychiatric disorders. Consequently the subcellular location of DISC1 is consistent with an involvement in the aetiology of major psychiatric illness.