title: 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.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, University of Santiago Hospital Complex, Santiago de Compostela, Spain. javier.costas@usc.es
authors.forename: Javier
authors.initials: J
authors.lastname: Costas
authors.forename: Noa
authors.initials: N
authors.lastname: Carrera
authors.forename: Eduardo
authors.initials: E
authors.lastname: Domínguez
authors.forename: Elisabet
authors.initials: E
authors.lastname: Vilella
authors.forename: Lourdes
authors.initials: L
authors.lastname: Martorell
authors.forename: Joaquín
authors.initials: J
authors.lastname: Valero
authors.forename: Alfonso
authors.initials: A
authors.lastname: Gutiérrez-Zotes
authors.forename: Antonio
authors.initials: A
authors.lastname: Labad
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000517:prevention & control; D012641:Selection, Genetic; D013030:Spain; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C493593:DRD3 protein, human; D050637:Receptors, Dopamine D3