A common haplotype of <Emphasis Type="Italic">DRD3</Emphasis> affected by recent positive selection is associated with protection from schizophrenia |
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Authors: | Javier Costas Noa Carrera Eduardo Domínguez Elisabet Vilella Lourdes Martorell Joaquín Valero Alfonso Gutiérrez-Zotes Antonio Labad Ángel Carracedo |
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Institution: | Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, University of Santiago Hospital Complex, Santiago de Compostela, Spain. javier.costas@usc.es |
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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 D3 receptor (DRD3) gene, by replication and pooled analysis with previous data (Mantel–Haenszel χ2
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.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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