Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response.

ABT-925, a selective dopamine D3 receptor (DRD3) antagonist, was tested in schizophrenia. A DRD3 gene polymorphism results in an S9G amino-acid change that has been associated with lower risk of schizophrenia, higher affinity for dopamine and some antipsychotics, and differential response to some antipsychotics. The effect of S9G genotype on response to ABT-925 was examined. DNA samples (N=117) were collected in a proof-of-concept, double-blind, randomized, placebo-controlled study of ABT-925 (50 or 150 mg QD) in acute exacerbation of schizophrenia. A pre-specified analysis assessed impact of genotype (SS versus SG+GG) on change from baseline to final evaluation for the Positive and Negative Syndrome Scale (PANSS) total score using analysis of covariance with genotype, treatment and genotype-by-treatment interaction as factors, and baseline score as covariate. Significant genotype-by-treatment interaction (P=0.015) was observed for change from baseline to final evaluation for the PANSS total score. Within subgroup analyses showed significant improvement from placebo in the SG+GG group treated with ABT-925 150 mg. More favorable clinical outcomes were observed in patients treated with ABT-925 150 mg who carried the DRD3 G allele than in those who carried the DRD3 SS genotype.

Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS data sets: STAR*D, Genetics of Recurrent Early-onset Depression and the publicly available Genetic Association Information Network-MDD data set. These data sets, totaling 3957 cases and 3428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500 K, and Perlegen). For each of 2.4 million HapMap II single-nucleotide polymorphisms (SNPs), using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P=6.78 x 10⁻7), SP4 (P=7.68 x 10⁻7) and GRM7 (P=1.11 x 10⁻6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N=2191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. On the basis of previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.