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.