Ethnic stratification of the association of RGS4 variants with antipsychotic treatment response in schizophrenia.
BACKGROUND
Genetic association studies, including a large meta-analysis, report association of regulator of G protein signaling 4 (RGS4) with schizophrenia in the context of heterogeneity. The central role of RGS4 in regulating signaling via Gi/o coupled neurotransmitter receptors led us to hypothesize that there may be RGS4 genotypes predictive of specific disease phenotypes and antipsychotic treatment responses.


METHODS
Subjects were 678 individuals with schizophrenia who participated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Among the 678 subjects, the inferred ancestries were 198 (29%) "Africa only," 397 (59%) "Europe only," and 83 (12%) "Other." Eight single nucleotide polymorphisms (SNPs) spanning RGS4 were genotyped. Multiple linear regression was used to analyze association of RGS4 markers with Positive and Negative Symptoms Scale (PANSS) scores at baseline and throughout antipsychotic treatment.


RESULTS
Two consecutive markers within RGS4, rs2661319 and rs2842030, were associated with more severe baseline PANSS total score. Treatment with perphenazine was more effective than treatment with quetiapine (p = .010) or ziprasidone (p = .002) in individuals of inferred African ancestry and homozygous for the rs951439 C allele.


CONCLUSIONS
RGS4 genotypes predicted both the severity of baseline symptoms and relative responsiveness to antipsychotic treatment. Although these analyses are exploratory and replication is required, these data provide support for RGS4 in schizophrenia pathogenesis and suggest a functional role for RGS4 in differential antipsychotic treatment efficacy of schizophrenia.
Campbell
Daniel B
DB
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, USA. daniel.campbell@vanderbilt.edu
Ebert
Philip J
PJ
Skelly
Tara
T
Stroup
T Scott
TS
Lieberman
Jeffrey
J
Levitt
Pat
P
Sullivan
Patrick F
PF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000627:therapeutic use; D003987:Dibenzothiazepines / Q000627:therapeutic use; D005006:Ethnicity; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D010546:Perphenazine / Q000627:therapeutic use; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D000069348:Quetiapine Fumarate; D020710:RGS Proteins / Q000235:genetics*; D012189:Retrospective Studies; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D020710:RGS Proteins; C098799:RGS4 protein; D000069348:Quetiapine Fumarate; D010546:Perphenazine