Genetic analysis of a candidate region for psychiatric illness on chromosone 4p

Abstract

Psychiatric illnesses are debilitating conditions for those affected and place a significant burden on the National Health Service, the social services and the family. Here I describe genetic analysis, physical mapping and transcript mapping of a region of chromosome 4p that is linked to psychiatric illness, including bipolar and unipolar affective disorders and schizophrenia.I have studied four families that show linkage of psychiatric illness to chromosome 4p. Linkage was first observed in a large family, F22, segregating bipolar affective disorder (BPAD) and recurrent major depression (RMD). Subsequently, a smaller family, F59, segregating affective disorders (Blackwood et al, 1996a), and two families (F50 & F48) segregating schizophrenia (SCZ), schizoaffective disorder and BPAD confirmed this linkage.Previously, comparison of the haplotypes inherited with illness in each family allowed prioritisation of two sub-regions for detailed study. Minimal Region One (MR1) is defined by overlap of the disease chromosomes from three Celtic families (F22, F59 & F50). Minimal Region Two (MR2) is defined by the two largest families F22 and F48, as well as F50. The sequence available from the human genome sequencing project for these two regions is largely complete. Here, I describe an extension to the BAC map in the repetitive telomeric end of MR1. The telomeric end of MR1 is defined by a recombination event in an individual from F50. I mapped clones, designed markers and refined the position of the recombination breakpoint. I also refined the position of the recombination breakpoint at the centromeric end of MR1, as defined by a member of F59.I describe construction of a transcript map of MR land 2 using bioinformatics methods, RT-PCR and cDNA library screening. I then selected two candidate genes from this region: orphan g-protein-coupled receptor 78 (GPR78) and superoxide dismutase 3 (SOD3), for further study. Firstly, I identified SNPs in the genes from the linked families, and then carried out a preliminary association study on 95 SCZ in patients, 93 BPAD patients 95 controls. The linkage disequilibrium (LD) between the markers was measured and, using a low stringency significant p-value cut off, revealed a positive association in GPR78. SNPs were then tested on a larger population for association. This work adds to the case for studying the role of chromosome 4 in the genetic susceptibility to affective disorder.