R. Mant

Disturbances in dopamine neurotransmission have been postulated to underlie schizophrenia. We report data from two independent studies of a BalI polymorphism in the dopamine D3 receptor gene in patients with schizophrenia. In both studies, more patients than controls were homozygous (p = 0.005, p = 0.008). When pooled data were analysed, this difference was highly significant (p = 0.0001) with a relative risk of schizophrenia in homozygotes of 2.61 (95% confidence intervals 1.60-4.26).

We have reported an association between schizophrenia and homozygosity of a Bal I polymorphism in the first exon of the dopamine D3 receptor gene (Crocq et al.: Journal of Medical Genetics 29:858-860, 1992). The present study consists of an attempt to replicate this finding in a further sample of 66 patients and 97 controls. Once again more patients than controls were homozygous, but the effect was not as strong as in our first study (chi 2 = 2.53, P = 0.05, one tailed). When pooled data from our two studies were analysed, excess homozygosity in patients remained highly significant (P = 0.002) with a particular excess of the 1:1 genotype (P = 0.01). This reflected a departure from Hardy-Weinberg equilibrium in the patients (P = 0.0005) but not the controls (P = 0.24). This led us to explore the possibility that there might be important differences between the patients in our two studies and that excess homozygosity might be a characteristic of particular subgroups of schizophrenics. Our findings suggest that the effect is consistently at its strongest in those patients who have a high familial loading and in those who have a good response to neuroleptic treatment, and that differences between our two samples might have contributed to the quantitatively different outcomes.

A collaboration involving four groups of investigators (Johns Hopkins University/Massachusetts Institute of Technology; Medical College of Virginia/The Health Research Board, Dublin; Institute of Psychiatry, London/University of Wales, Cardiff; Centre National de la Recherche Scientifique, Paris) was organized to confirm results suggestive of a schizophrenia susceptibility locus on chromosome 22 identified by the JHU/MIT group after a random search of the genome. Diagnostic, laboratory, and analytical reliability exercises were conducted among the groups to ensure uniformity of procedures. Data from genotyping of 3 dinucleotide repeat polymorphisms (at the loci D22S268, IL2RB, D22S307) for a combined replication sample of 256 families, each having 2 or more affected individuals with DNA, were analysed using a complex autosomal dominant model. This study provided no evidence for linkage or heterogeneity for the region 22q12-q13 under this model. We conclude that if this region confers susceptibility to schizophrenia, it must be in only a small proportion of families. Collaborative efforts to obtain large samples must continue to play an important role in the genetic search for clues to complex psychiatric disorders such as schizophrenia.