Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population

Haploinsufficiency for or mutation in at least one gene from the velocardiofacial syndrome (VCFS) region at chromosome 22q11 is implicated in psychosis. Linkage disequilibrium mapping of the region in patients identified a segment containing two genes, proline dehydrogenase (PRODH) and DGCR6, as candidates [Liu et al., 2002a] and by analysis of additional polymorphisms the PRODH gene was associated with schizophrenia in adult and early onset patients. In the present study we provide additional evidence in support of genetic association between PRODH and schizophrenia in a Chinese population. We analyzed the PRODH gene in a samples of schizophrenic patients and their families from Sichuan, SW China consisting of 528 family trios and sibling pairs. We genotyped six SNPs, PRODH*1195C-->T, PRODH* 1482C-->T, PRODH*1483A-->G, PRODH* 1766A-->G, PRODH*1852G-->A PRODH*1945T-->C, two of which (PRODH*1483A-->G and PRODH* 1852G-->A) have not been previously reported. We found association with schizophrenia for two haplotypes consisting of PRODH*1945T-->C and PRODH*1852G A (Global P=0.006), and PRODH*1852G.A and PRODH*1766A-->G (Global P = 0.01) which include one of the newly identified markers. After six-fold Bonferroni correction for multiple testing the PRODH*1945T-C/PRODH*1852G-->A haplotypes remained significant. This is a sub-haplotype of the PRODH haplotype previously associated with schizophrenia and it also maps to the 3' region of the gene, indicating that this is the region most likely to contain the underlying risk alleles. Overall this finding supports a role for the PRODH locus in schizophrenia.