A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes

摘要

Background: The gene coding for the D2 dopamine receptor (DRD2) is considered to be one of the most pertinent candidate genes in schizophrenia. However, genetic studies have yielded conflicting results whereas the promising TaqlA variant/rsl 800497 has been mapped in a novel gene, ANKK1. Methods: We investigated eleven single nudeotide polymorphisms (SNPs) spanning the DRD2 and ANKK1 genes, using both a case-control association study comparing 144 independent patients to 142 matched healthy subjects, and a transmission disequilibrium test in 108 trios. This classical genetic study was coupled with a cladistic phylogeny-based association test of human variants, and with an interspecies evolution study of ANKK1.Results: Case-control study, followed by a 108 trios family-based association analysis for replication, revealed an association between schizophrenia and the ANKK1 rsl 800497 (p = 0.01, Odds Ratio = 1.5,95% Confidence Interval = 1.1-2.2), and the intergenic rs2242592 (p = 2-10~4, OR = 1.8, 95%CI = 1.3-2.5). A significant SNP-SNP interaction was also found (p<10~5, OR = 2.0,95%CI = 1.6-2.5). The phylogeny-based association test also identified an association between both these polymorphisms and schizophrenia. Finally, interspecies comparison of the sequences from chimpanzee, orangutan, rhesus macaque and human species suggested specific involvement of ANKK1 in the human lineage.Conclusions: Intergenic rs2242592 appears to be involved in the genetic vulnerability to schizophrenia, whereas the ANKKi rsl 800497 appears to have a modifying rather than causative effect. Finally, ANKK1 may be a specific human lineage-trait involved in a specific human disease, schizophrenia.