Crocq et al. (1992) presented data from 2 independent studies carried out in the UK and France, determining frequencies of a BalI polymorphism, ser9-to-gly (S9G), in the DRD3 gene in patients with schizophrenia (181500). In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analyzed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% CI = 1.60-4.26).
Nothen et al. (1993) and Nanko et al. (1993) were unable to confirm the finding by Crocq et al. (1992) of an association between schizophrenia and homozygosity at the DRD3 receptor locus. However, Spurlock et al. (1998) did replicate the findings of Crocq et al. (1992) as part of the European Multicentre Association Study of Schizophrenia. An excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi(2), 8.54, P = 0.003; odds ratio, 1.64, 95% CI, 1.18-2.29).
Lucotte et al. (2006) found that the DRD3 gly9 allele cosegregated with hereditary essential tremor (ETM1; 190300) in 23 of 30 unrelated French families. Parametric linkage analysis and transmission disequilibrium testing also showed significant positive association between the polymorphism and essential tremor. Among probands, gly9 homozygotes had significantly younger age at onset and more severe symptoms compared to heterozygotes, suggesting a gene dosage effect. Lucotte et al. (2006) noted that S9G occurs in the extracellular N terminus of the protein, which may increase dopamine affinity and efficacy. The authors hypothesized that essential tremor may result from a gain-of-function mechanism. By in vitro functional analysis in human embryonic kidney cells, Jeanneteau et al. (2006) found that the DRD3 gly9 allele had increased dopamine affinity, resulting in an increased intracellular response and prolonged protein kinase signaling compared to the ser9 allele, confirming a gain-of-function effect.
Tan et al. (2007) did not find an association between the gly9 allele and essential tremor among 163 sporadic Asian patients or 16 Asian families with essential tremor.
