A genetic schizophrenia-susceptibility region located between the ANKK1 and DRD2 genes.
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 TaqIA variant/rs1800497 has been mapped in a novel gene, ANKK1.


METHODS
We investigated eleven single nucleotide 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 rs1800497 (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 ANKK1 rs1800497 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.
Dubertret
Caroline
C
INSERM U894 (exU675), Center of Psychiatry and Neurosciences, Paris, France. caroline.dubertret@lmr.aphp.fr
Bardel
Claire
C
Ramoz
Nicolas
N
Martin
Pierre-Marie
PM
Deybach
Jean-Charles
JC
Adès
Jean
J
Gorwood
Philip
P
Gouya
Laurent
L
D000367:Age Factors; D000818:Animals; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D019143:Evolution, Molecular; D005192:Family Health; D005260:Female; D005602:France; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D002679:Pan troglodytes; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D057079:Pongo; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*
D017448:Receptors, Dopamine D2; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases