A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia

Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, University of Santiago Hospital Complex, Santiago de Compostela, Spain.
Human Genetics (Impact Factor: 4.82). 12/2008; 124(6):607-13. DOI: 10.1007/s00439-008-0584-7
Source: PubMed


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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    • " neurodevelopmental disorders , including schizophre - nia ( Rodenas - Cuadrado et al . , 2014 ) . In addition , this gene presents signatures of recent positive selection in humans ( Ayub et al . , 2013 ) . The role of recent positive selection in the spread of schizophrenia susceptibility haplotypes has been shown at other genes , such as DRD3 ( Costas et al . , 2009 ) , MAOB ( Carrera et al . , 2009 ) , or AHI1 ( Torri et al . , 2010 ) . The transcription factor TCF4 constitutes another example of a gene with unusual evolution at regulatory regions that increases risk to schizophrenia and is involved in neurodevelopment ( Stefansson et al . , 2009 ; Steinberg et al . , 2011 ) . Thus , it presents a"
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    ABSTRACT: Schizophrenia may be considered a human-specific disorder arisen as a maladaptive by-product of human-specific brain evolution. Therefore, genetic variants involved in susceptibility to schizophrenia may be identified among those genes related to acquisition of human-specific traits. NPAS3, a transcription factor involved in central nervous system development and neurogenesis, seems to be implicated in the evolution of human brain, as it is the human gene with most human-specific accelerated elements (HAEs), i.e., .mammalian conserved regulatory sequences with accelerated evolution in the lineage leading to humans after human-chimpanzee split. We hypothesize that any nucleotide variant at the NPAS3 HAEs may lead to altered susceptibility to schizophrenia. Twenty-one variants at these HAEs detected by the 1000 genomes Project, as well as five additional variants taken from psychiatric genome-wide association studies, were genotyped in 538 schizophrenic patients and 539 controls from Galicia. Analyses at the haplotype level or based on the cumulative role of the variants assuming different susceptibility models did not find any significant association in spite of enough power under several plausible scenarios regarding direction of effect and the specific role of rare and common variants. These results suggest that, contrary to our hypothesis, the special evolution of the NPAS3 HAEs in Homo relaxed the strong constraint on sequence that characterized these regions during mammalian evolution, allowing some sequence changes without any effect on schizophrenia risk. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "Therefore, analyses of functional candidate genes undergoing recent natural selection may derive new common susceptibility (or protective) alleles for human phenotypes. It has been suggested that a common haplotype of DRD3 affected by recent positive selection is associated with protection from SZ in a European population, and that the selection acts most probably on rs6280 [Costas et al., 2009]. However, it remains unknown whether such selective pressure acts on Asian populations. "
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    ABSTRACT: The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C-allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene.
    Full-text · Article · Jul 2011 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "In both CEU and YRI signatures, diverse disease categories such as cardiovascular, immunological, neurological, and skeletal and muscular diseases showed high associations (Table 2). This result attracted us because a number of individual studies have discovered population-specific loci susceptibility to, for example, cardiovascular diseases [10,22], schizophrenia [23], Crohn's disease [24-26] and diabetes [12,26,27], and have suggested they are consequences of natural selection. In addition, although the underlying mechanism has not been clarified, some previous genome-wide studies have reported an association between recent selection and the biological functions of skeletal development, brain development, and immune response [5,16]. "
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    ABSTRACT: The creation of a coherent genomic map of recent selection is one of the greatest challenges towards a better understanding of human evolution and the identification of functional genetic variants. Several methods have been proposed to detect linkage disequilibrium (LD), which is indicative of natural selection, from genome-wide profiles of common genetic variations but are designed for large regions. To find population-specific LD within small regions, we have devised an entropy-based method that utilizes differences in haplotype frequency between populations. The method has the advantages of incorporating multilocus association, conciliation with low allele frequencies, and independence from allele polarity, which are ideal for short haplotype analysis. The comparison of HapMap SNPs data from African and Caucasian populations with a median resolution size of ~23 kb gave us novel candidates as well as known selection targets. Enrichment analysis for the yielded genes showed associations with diverse diseases such as cardiovascular, immunological, neurological, and skeletal and muscular diseases. A possible scenario for a selective force is discussed. In addition, we have developed a web interface (ENIGMA, available at, which allows researchers to query their regions of interest for population-specific LD. The haplotype entropy method is powerful for detecting population-specific LD embedded in short regions and should contribute to further studies aiming to decipher the evolutionary histories of modern humans.
    Full-text · Article · Apr 2010 · BMC Genetics
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