Xiao Y. Dai

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the Taq1A polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

A study of the association between schizophrenia and the dopamine D3 receptor gene

A study of the genetic association between schizophrenia and aBalI polymorphism in exon 1 of the dopamine D3 (DRD3) gene, a candidate gene for schizophrenia, was conducted. The polymorphism was examined in 91 patients whose symptoms satisfied DSM-III-R for schizophrenia and 90 controls. There were no significant differences between the groups in allele frequencies or genotype counts. Contrary to a previous report, the patients were no more likely to be homozygous than controls. Moreover, no association with the presence of illness could be demonstrated when the patients were grouped according to sex, age of onset, history of admission to psychiatric institutions or positive family history.

Neurotrophin-3 gene polymorphism associated with schizophrenia.

The recent possible neurodevelopmental etiology of schizophrenia makes the neurotrophin‐3 (NT‐3) gene an interesting candidate locus. We studied the allelic distributions of dinucleotide repeat polymorphism at the NT‐3 gene locus in 70 patients with schizophrenia and in 70 controls. A highly significant difference between the two groups was observed at the allele A3. Even Bonferronis correction was used, the difference was still significant. Individuals with homozygous or heterozygous for the allele A3 had a 2.4‐fold increased risk of schizophrenia. Determination of NT‐3 genotype may help to identify those at greater risk of schizophrenia. Furthermore, this finding supports evidence implicating neurodevelopmental deficit in the pathogenesis of this disorder.

Linkage studies between affective disorder and dopamine D2, D3, and D4 receptor gene loci in four Japanese pedigrees

Dopamine antagonists are effective in the treatment of episodes of acute mania. Conversely, drugs which increase dopamine activity can induce a switch to mania. Therefore, disturbances in dopamine transmission and dopamine receptors might be implicated in the pathophysiology of bipolar affective disorder. We have carried out linkage studies between the susceptibility gene for effective disorder and polymorphisms of dopamine DRD2, DRD3, and DRD4 receptor genes in four Japanese pedigrees. Linkages of both DRD2 and DRD3 have been excluded, at least for dominant and intermediate models. The result for DRD2 was consistent with previous studies. For DRD3 this is the first exclusion of affective disorder from this locus in the 3q13.3 where DRD3 has been localized. On the other hand, our data could not exclude linkage of DRD4.

No evidence of linkage or allelic association of schizophrenia with DNA markers at pericentric region of chromosome 9

Based on our previous study suggesting the pericentric region of chromosome 9 as of potential importance in schizophrenia, we have carried out a linkage study between the schizophrenia phenotype and the dinucleotide repeat polymorphisms D9S55, D9S15, and D9S202 in three pedigrees multiply affected with schizophrenia. In addition, we have conducted allelic association studies using 60 patients with schizophrenia and 60 controls with polymorphisms at D9S55 and D9S15 markers. No evidence for linkage or association was found. The results indicate that susceptibility genes for schizophrenia are less likely to be located at the pericentric region of chromosome 9, assuming genetic homogeneity of the pedigrees.

Screening for mutations at codon 717 of the amyloid precursor protein gene in Alzheimer's disease

Abstract Three kinds of missense mutation at codon 717 of amyloid precursor protein (APP) gene (Val→Ile; Val→Gly; Val→Phe) were screened in 114 patients with familial and sporadic Alzheimers disease (AD), using a rapid testing method for each Val→Gly and Val→Phe mutation and Goates method for Val→Ile mutation based on the polymerase chain reaction. Mutations were not found in the subjects, confirming earlier suggestions that these three mutations at codon 717 of APP gene account for only a small proportion of cases of not only familial AD but also sporadic AD.

No association between c‐fos gene polymorphisms and sporadic Alzheimer's disease

Abstract Although ApoE ε4 is a major risk factor for sporadic Alzheimers disease (AD), 20–30% of sporadic AD patients do not have this allele. This indicates that other risk factors are involved in the pathogenesis of sporadic AD. Studies of the genetic association between AD and polymorphisms in the c‐fos gene, a candidate gene for AD, were conducted. The polymorphisms of Dsal in exon 2 and Sau3Al in intron 2 were examined in 89 patients diagnosed as sporadic cases of probable AD clinically and radiologically according to the NINCDS‐ADRDA criteria. This was also undertaken in 96 controls. There was no significant difference between the groups in allele frequencies or genotype counts. Although c‐fos gene as a locus conferring susceptibility to sporadic AD cannot be ruled out, these data could not support the hypothesis that a c‐fos allele should be another risk factor for sporadic AD.