CLINICAL AND FUNCTIONAL CORRELATES OF A DOPAMINE D3 RECEPTOR POLYMORPHISM

This is a review of our research on dopamine receptor D3 (DRD3) gene polymorphism in psychiatric patients. We found that heterozygosity at a diallelic Ball polymorphic site in the first exon of the DRD3 gene was associated with schizophrenia, as did another group (Mant et al., 1994). However others did not reproduce our findings and raised doubts about a possible role of the DRD3 in schizophrenia. More recently, we found that homozygosity for allele 2 at the same site was associated with lower cortisol and ACTH responses to apomorphine. We had also previously reported lower ACTH and cortisol responses to apomorphine in paranoid schizophrenics compared to controls (Mokrani et al., in press). This suggests that DRD3 polymorphisms might be associated with functional differences that could secondarily influence the expression of schizophrenia, in spite of the lack of clear association with schizophrenia. More generally, classical association studies may be limited in their power to prove or disprove minor gene effects in schizophrenia because the disorder is heterogeneous and various genes may have additive effects in different patients. Biological measures that are closer to gene effects may be a better way to test candidate genes than the association with a complex clinical phenotype.