Association analysis of the glial cell line-derived neurotrophic factor (GDNF) gene in schizophrenia

The glial cell line-derived neurotrophic factor (GDNF) gene is located within a region of chromosome 5 (5p14.1-q13.3) that has been highlighted as a potential schizophrenia susceptibility locus by a number of genome scans. GDNF is neurotrophic and is also thought to be involved in differentiation of dopaminergic neurones. The GDNF gene is, therefore, a positional and functional candidate gene for schizophrenia. It is of additional interest because altered GDNF mRNA and protein expression has been reported in response to antipsychotics and the psychotomimetic phencyclidine, and two previous studies, focussed on a single variant, have reported weak support for genetic association between GDNF and schizophrenia in small samples. To test the hypothesis that GDNF is a susceptibility gene for schizophrenia, we performed a detailed association study. We chose 9 SNPs that spanned a genomic region of 40 kb and fully encompassed GDNF. SNPs were genotyped in a sample of 673 schizophrenic patients and 716 matched controls, all of Caucasian origin and all collected from the UK or Ireland. Of the 9 SNPs genotyped 2 showed nominally significant genotypic association at the P< or =0.05 level (rs2973050; OR=1.11; P-value=0.007 and rs2910702; OR=1.14; P-value=0.039). Permutation testing to allow for multiple comparisons of non-independent markers gave a corrected genotypic P-value of 0.052 for rs2973050. We also genotyped an (AGG)(n) repeat located in the 3' UTR of the GDNF but this showed no evidence for association. We conclude that our sample does not provide independent statistically significant evidence for association between GDNF and schizophrenia, nor does it replicate previous specific reports of association.