Lack of association between VNTR polymorphism of dopamine transporter gene (SLC6A3) and schizophrenia in a Brazilian sample

Abstract

-A role of dopaminergic dysfunction has been postulated in the aetiology of schizophrenia. We hypothesized that variations in the dopamine transporter gene (SLC6A3) may be associated with schizophrenia. We conducted case-control and family based analysis on the polymorphic SLC6A3 variable number tandem repeat (VNTR) in a sample of 220 schizophrenic patients, 226 gender and ethnic matched controls, and 49 additional case-parent trios. No differences were found in allelic or genotypic distributions between cases and controls and no significant transmission distortions from heterozygous parents to schizophrenic offspring were detected. Thus, our results do not support an association of the SLC6A3 VNTR with schizophrenia in our sample.KEY WORDS: DAT1, SLC6A3, schizophrenia, genetic polymorphism, genetic association, trios. Ausência de associação entre o polimorfismo VNTR do gene do transportador de dopamina (SLC6A3) e esquizofrenia em uma população brasileiraRESUMO -Genes do sistema dopaminérgico são de escolha para a pesquisa de susceptibilidade para a esquizofrenia. Desse modo, possível contribuição do polimorfismo do gene do transportador de dopamina (SLC6A3) no aumento da vulnerabilidade para a esquizofrenia foi investigada no presente estudo. Analisou-se a distribuição do sítio polimórfico do gene do transportador de dopamina (VNTR) em uma população de 220 pacientes com esquizofrenia (critério diagnóstico: DSM-IV) e comparou-se com a distribuição em uma população controle de 226 indivíduos pareados para sexo e etnia. Nenhuma diferença foi observada na distribuição dos alelos entre casos e controles. O mesmo polimorfismo também foi investigado em uma segunda amostra composta por 49 trios (pais e probando). O resultado também foi negativo. Tais dados não dão suporte para a participação do polimorfismo do gene do transportador de dopamina no aumento de susceptibilidade para esquizofrenia na amostra estudada. PALAVRAS-CHAVE: DAT1, SLC6A3, esquizofrenia, polimorfismo genético, associação genética, trios. Schizophrenia (SCZ) affects some 1% of the general population. Epidemiological studies have indicated a strong genetic component in the pathogenesis of SCZ and heritability estimates as high as 80% have been reported 1 . Pharmacological evidence suggests an involvement of the dopaminergic system as many antipsychotic drugs block dopamine receptors in the brain and are highly effective in treating symptoms of SCZ 2 . Further, amphetamines and cocaine tend to provoke or exarcebate psychotic symptoms in susceptible individuals by preventing dopamine re-uptake 3 . L-DOPA has also been implicated in psychotic symptoms through variable release of dopamine into the synapse 4 . Therefore, genes involved in the dopaminergic system are potential targets for genetic association studies with SCZ 5 .Polymorphisms in dopamine receptors have been widely examined, but the results have been inconclusive [6][7][8][9][10][11][12] . Another possible candidate is the dopamine transporter gene (SLC6A3 or DAT1). The dopamine tran...

A review of psychiatric genetics research in the Brazilian population

“…27 The same group (PROGENE) investigated polymorphisms from dopaminergic, noradrenergic and serotonergic genes (Ser-9-Gly DRD3 gene, VNTR DAT1 gene, 1287 A/G norepinephrine transporter/NET gene, G681C serotonin receptor/5-HT1Dbeta gene, C516T serotonin receptor/5-HT2A gene) and failed to find an association with SCZ. [28][29][30][31][32] In two studies, Oliveira et al addressed if a polymorphism in the promoter region of the SLC6A4 could be implicated in SCZ, BPD and dysthymia. 33,34 However, in both studies, there was no difference in alleles (long/short) neither in genotypes frequencies between any of the groups of patients and controls.…”

Association study between the rs165599 catechol-O-methyltransferase genetic polymorphism and schizophrenia in a Brazilian sample

“…Therefore, the genes involved in the dopaminergic system are potential targets for genetic association investigations in schizophrenia. Polymorphisms in dopamine transporter and receptors genes have been widely investigated as risk factors for schizophrenia development, but the results have been inconclusive [2][3][4][5] . Thus, other possible candidates for such investigations are the enzymes that metabolize dopamine, such as catechol-O-methyltransferase (COMT).…”

Association study between the Taq1A (rs1800497) polymorphism and schizophrenia in a Brazilian sample

“…Some of the most investigated genes in studies of vulnerability to schizophrenia are those that code for proteins of the dopaminergic system because the evidences of the role of central dopamine pathways in the pathophysiology of the disorder 3,4,5,6,7 . Central nervous stimulant drugs, that block reuptake of dopamine or facilitate its release on neuronal synapses, may cause psychotic symptoms 8 .…”