Dopamine D4 and D5 receptor gene variant effects on clozapine response in schizophrenia: Replication and exploration

• Published in: Progress in neuro-psychopharmacology & biological psychiatry Vol. 37; no. 1; pp. 62 - 75
• Main Authors: Hwang, Rudi, Tiwari, Arun K., Zai, Clement C., Felsky, Daniel, Remington, Eli, Wallace, Tessa, Tong, Ryan P., Souza, Renan P., Oh, Gabriel, Potkin, Steven G., Lieberman, Jeffrey A., Meltzer, Herbert Y., Kennedy, James L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 27.04.2012
• Subjects: African Continental Ancestry Group - genetics; Antipsychotic; Antipsychotic Agents - therapeutic use; Clozapine; Clozapine - therapeutic use; Dopamine D4 receptor gene (DRD4); Dopamine D4 receptors; Dopamine D5 receptor gene (DRD5); Dopamine D5 receptors; European Continental Ancestry Group - genetics; Exons; Exploration; Female; Gene polymorphism; Genetic Variation - genetics; Genotyping; Humans; Introns; Male; Mental disorders; Microsatellites; Neuroleptics; Pharmacogenetics; Polymorphism, Single Nucleotide - genetics; Prospective Studies; Receptors, Dopamine D4 - genetics; Receptors, Dopamine D5 - genetics; Replication; Response; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - ethnology; Schizophrenia - genetics; Single-nucleotide polymorphism; Statistics; Treatment Outcome; ADHD; Dopamine D5 receptor gene (DRD5); ABI; dNTP; mRNA; SCZ; cAMP; PFC; bp; (2–8)R; BPRS; CLZ; ANCOVA; YRI; DRD(1–5); SNP; Sp1; Antipsychotic; DSM; IHMP; Pharmacogenetics; OR; d; CAMH; NEB; Clozapine; BPOS; AP; Response; BNEG; D(1–5); CEU; DNA; Dopamine D4 receptor gene (DRD4); LD; DA; PCR
• ISSN: 0278-5846; 1878-4216; 1878-4216
• DOI: 10.1016/j.pnpbp.2011.11.018

This study aimed to: 1) replicate previously reported associations between dopamine D4 receptor gene (DRD4) polymorphisms and antipsychotic (AP) response in a clozapine (CLZ) response sample; and 2) explore possible associations of polymorphisms across dopamine D5 receptor gene (DRD5) as well as other DRD4 regions. DRD4 exon III 48-bp, intron I (G)n, and 120-bp repeat polymorphisms, and three DRD4 single nucleotide polymorphisms (SNPs); and DRD5 (CA/CT/GT)n microsatellite and four DRD5 SNPs were assessed using standard genotyping and statistical procedures. We report evidence, which does not survive correction for multiple testing, supporting previous DRD4 findings. Findings of interest include the 120-bp 1-copy allele, intron I (G)n 142-bp/140-bp genotype, and exon III 4R allele with CLZ response. All DRD5 tests were negative. Overall, these results suggest a possible minor contribution of DRD4 variants, but not DRD5 variants, towards the AP/CLZ response phenotype. ►DRD4 exon III polymorphism 4R allele associated with better CLZ response. ►Ozdemir's (1999) finding of DRD4 (G)n genotype with poor CLZ response replicated. ►Positive finding for DRD4 120-bp repeat polymorphism; supports Thomas et al. (2008). ►No associations observed between DRD5 polymorphisms and CLZ response. ►Further study of DRD4 exon III and lesser studied DRD4 variants is warranted.