A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia.
ABSTRACT The number and frequency of susceptibility alleles at loci associated to most psychiatric disorders is largely unknown, in spite of its relevance for the design of studies aiming to find these alleles. Both, common polymorphisms and rare mutations may contribute to the genetic susceptibility to complex psychiatric disorders, being the relative relevance of each type of variation currently under debate. Here, we confirmed the existence of a common protective haplotype against schizophrenia at the dopamine D(3) receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel-Haenszel chi(2) P value = 0.00227; OR = 0.79, 95% CI 0.68-0.92, based on 794 cases and 1,078 controls from three independent populations of European origin). This protective haplotype is at very low frequency in Sub-Saharan Africans (median 0.06) and at intermediate frequencies in other populations (median 0.25). We also revealed, by examining the patterns of linkage disequilibrium around this gene, that the protective haplotype has reached high frequency in non-African populations due to selection acting, most probably, on a linked functional polymorphism, the non-synonymous single nucleotide polymorphism Ser9Gly (rs6280), also at DRD3. Thus, this finding shows that the natural selection may play a role in the existence of common alleles conferring different susceptibility to schizophrenia.
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ABSTRACT: Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [(11)C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis.PLoS ONE 01/2013; 8(1):e54108. · 3.53 Impact Factor
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ABSTRACT: Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed.Journal of Psychiatric Research 08/2013; · 4.09 Impact Factor
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ABSTRACT: The dopamine receptor gene DRD3 and in particular the single nucleotide polymorphism Ser9Gly has been extensively investigated and found to have potential association with a wide variety of conditions. These include essential tremor, unipolar and bipolar depression, as well as a loose association with schizophrenia. Evaluation of (1) these known associations with DRD3, (2) the recent finding of Costas and colleagues that a haplotype containing Ser-9 is associated with protection from schizophrenia, and (3) an extant trait model of personality, leads to the hypothesis that an allele DRD3/Ser codes for trait aggression by Mendelian recessive inheritance. The implications of this hypothesis are that (1) DRD3 is a pleiotropic gene having allelic polymorphism related to both behavior and disease, and (2) models of personality based on genetic traits hold promise. In the area of schizophrenia, the hypothesis implies that schizophrenic patients can be divided into two broad classes: those having genotype DRD3/Ser/Ser and those who lack this homozygosity. The hypothesis of the association of DRD3 with trait aggression could be readily evaluated by testing groups of healthy individuals by personality inventory focused on aggression and by biochemical assay of neurotransmitter levels.Medical Hypotheses 09/2011; 77(6):1108-10. · 1.18 Impact Factor