title: Sexually dimorphic interaction between the DRD1 and COMT genes in schizophrenia.
abstract: Dopaminergic dysfunction in the prefrontal cortex (PFC) is involved in the pathophysiology of schizophrenia. In the PFC, dopamine signalling largely depends on the D1 receptors, which are coded by the DRD1 gene, and on the regulation of dopamine levels by the enzyme catechol-O-methyltransferase (COMT). Here, we investigate the role of DRD1 and its interaction with the COMT gene in schizophrenic patients. In two gender-limited independent patient and control samples, we genotype five Tag single nucleotide polymorphisms (tagSNPs) of DRD1. The DRD1 SNP and haplotype associations, as well as interaction effects with the Val158Met COMT SNP were analyzed. In the male sample, we found the rs11746641 and rs11749676 DRD1 SNPs were associated with schizophrenia. Haplotype analyses identified the T-A-T-C-T variant related to a protective effect (P = 0.008) and the G-G-T-C-C variant that showed a tendency to be a risk factor for the disorder (P = 0.012). A logistic regression analysis revealed a significant pattern of interaction between DRD1 and COMT for both the rs11746641 (P = 0.002) and rs11749676 (P = 4.5 x 10(-5)) SNPs. DRD1-associated haplotypes were exclusively related to schizophrenia in the Val homozygous subgroup of patients (T-A-T-C-T: P = 0.003; G-G-T-C-C: P = 0.006). In females, none of the DRD1 SNPs were linked to the disorder. Our genetic data suggest that DRD1 and COMT are epistatically associated with protection against and the risk of developing schizophrenia in a gender-dependent fashion, and support the role of dopamine dysfunction at the PFC in the pathophysiology of this disorder.
authors.affiliation: Servicio de Psiquiatría, Hospital Universitario 12 de Octubre, Madrid, Spain. jhoenicka@gmail.com
authors.forename: Janet
authors.initials: J
authors.lastname: Hoenicka
authors.forename: Elena
authors.initials: E
authors.lastname: Garrido
authors.forename: Guillermo
authors.initials: G
authors.lastname: Ponce
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodríguez-Jiménez
authors.forename: Isabel
authors.initials: I
authors.lastname: Martínez
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rubio
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Jiménez-Arriero
authors.forename: Tomás
authors.initials: T
authors.lastname: Palomo
mesh_terms: D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000235:genetics; D005260:Female; D005796:Genes; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D017447:Receptors, Dopamine D1; D002394:Catechol O-Methyltransferase; D004298:Dopamine