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

Costas, Javier, Carrera, Noa ORCID:, Domínguez, Eduardo, Vilella, Elisabet, Martorell, Lourdes, Valero, Joaquín, Gutiérrez-Zotes, Alfonso, Labad, Antonio and Carracedo, Ángel 2009. A common haplotype of DRD3 affected by recent positive selection is associated with protection from schizophrenia. Human Genetics 124 (6) , pp. 607-613. 10.1007/s00439-008-0584-7

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Subjects: R Medicine > R Medicine (General)
Publisher: Springer
ISSN: 0340-6717
Last Modified: 31 Oct 2022 10:30

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