No association between 12 dopaminergic genes and schizophrenia in a large Dutch sample

Abstract

It has been suggested that genes involved in dopamine neurotransmission contribute to the pathogenesis of schizophrenia. However, reported associations of the disorder with genetic markers in dopaminergic genes have yielded inconsistent results. Possible explanations are differences in phenotyping, genetic heterogeneity, low marker informativity, and the use of small sample sizes. Here, we present a two-stage analysis of 12 dopaminergic genes in a large sample of Dutch schizophrenic patients. To reduce genetic heterogeneity, only patients with at least three Caucasian grandparents of Dutch ancestry were ascertained. An efficient genotyping strategy was used, in which polymorphic microsatellite markers were first screened for association in DNA pools. Promising results were followed up by individual genotyping in an extended sample. The pooled samples consisted of 208 schizophrenic patients and 288 unmatched control individuals. For each of the genes, more than one microsatellite marker was selected where possible, either intragenic or close to the gene. After correcting for multiple testing, significantly different allele frequencies were detected for DRD5 marker D4S615. Subsequently, we individually genotyped this particular marker and another DRD5 marker, as well as a DRD3 marker that could not be analyzed using the pooling strategy. This was done in an extended sample of 282 schizophrenic patients and a control sample of 585 individuals. In this second stage of the study, we found no association between these three markers and schizophrenia. The results of our comprehensive analysis provide no evidence for association between schizophrenia and 12 dopaminergic genes in a large Dutch sample.

Meta-analysis shows association between the tryptophan hydroxylase (TPH) gene and schizophrenia

“…For TPH, two studies (Nolan et al 2000;Segman et al 2003) were excluded because controls were patients; one (Serretti et al 1999) was discarded because it was an association study on psychotic symptomatology; one was discarded because of unclear alleles and one (Semwal et al 2001) for non-case-control design. For TH, one study (Hoogendoorn et al 2005) was discarded because of insuYcient data [the data of Hoogendoorn et al (2005) and Semwal et al (2002)] were omitted because we were unable to contact the authors), and one (Thibaut et al 1997) was excluded because it dealt with demographic and clinical comparisons among patients and one (Chao and Richardson 2002) because it investigated other polymorphisms. In the end, 22 studies, composed of 7 studies for TPH, 13 for TH, and 2 for PAH, met our criteria for inclusion (Table 1).…”

Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia

“…The 1.24-fold decrease in the DDC gene reported herein in PCP-SI rats is also unsurprising. Polymorphisms in DDC, the gene the encoding dopa decarboxylase which converts L-DOPA into dopamine, have been associated with the age of onset of schizophrenia in male patients (Borglum et al, 2001), although other studies found no association in paranoid schizophrenia (Hoogendoorn et al, 2005; Talkowski et al, 2008). …”

Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia

“…Nevertheless, case-control genetic association studies analyzing the role of DRD1 in schizophrenia have revealed negative results [Campion et al, 1994;Cichon et al, 1996;Kojima et al, 1999;Iwata et al, 2003;Hoogendoorn et al, 2005;Dmitrzak-Weglarz et al, 2006;Dolzan et al, 2007;Talkowski et al, 2008].…”