An investigation into the genetic basis of schizophrenia
Schizophrenia is a common and debilitating mental illness, affecting 1% of the population and affecting all ethnic groups (Wilkinson et al 1996). It is a highly complex disorder containing genetic and environmental components (Birkett et al. 2000), making it difficult to identify those genes responsible for the development of schizophrenia using linkage alone. This thesis presents work on three candidate genes Disrupted in Schizophrenia 1 (DISC1), Neuregulin 1 (NRG1) and 5-HT5A, using a case control approach to test for association between schizophrenia and the candidate genes, in the Scottish population. All findings for 5-HT5A were negative. The exact function of DISC1 is unknown but it appears to have a role in neurodevelopment. Acting in complex with NUDEL to affect neurite growth (Ozeki et al. 2003) and modifying Translin binding when intragenically spliced with TRAX (Chennathukuzhi et al. 2001). Genotypic and haplotypic analysis of DISC1 using a combination of pooling and individual genotyping. Led to the discovery of a novel nonsynonymous SNP A40961G located in exon 2 of DISC1 which shows significant association with schizophrenia (p = 0.000232, O.R. = 0.71861, n = 600). Haplotypic analysis identified a 4 marker at-risk haplotype (p = 0.0010, O.R = 2.56, n = 200) containing the A40961G marker. NRG1 was investigated at the request of DeCode Genetics in order to replicate there positive at the 5' end of NRG1 (p = 0.000087) (Stefansson et al. 2002). The genotyping was carried out blind of diagnosis by myself at DeCode Genetics, analysis was carried out independently. The results confirmed the Icelandic findings for a 7 marker at-risk haplotype located at the 5' end NRG1 (p = 0.00031).