Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

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The influences of CYP2C9*3 and VKORC1-1639G>A on the maintenance dose of warfarin were well-defined in Japanese patients, while polymorphisms of GGCX and FVII did not affect it. The model established in this study might provide us most likely individual maintenance dose based on clinical and genetic backgrounds.

No positive association between adrenergic receptor variants of a 2c Del322-325, b 1 Ser49, b 1 Arg389 and the risk for heart failure in the Japanese population Department of Internal Medicine and Cardiology, Osaka City University School of Medicine, Osaka, Japan AimsWe investigated the correlation of adrenergic receptor polymorphisms, a 2c Del322-325, b 1 Ser49Gly and b 1 Arg389Gly, with the risk of heart failure in the Japanese population. MethodsThese polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control g roup. ResultsThere were no differences or any trends in the allele and genotype frequencies of the b 1 Ser49Gly and b 1 Arg389Gly polymorphisms. The allele frequency of the a 2c Del322-325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance ( P = 0.022 > 0.017, by Bonferroni correction). ConclusionsIn this population, the variants b 1 Ser49, b 1 Arg389, and a 2c Del322-325 do not appear to be risk factors for chronic heart failure due to DCM. The a 2c Del322-325 variant may in fact confer some protection. IntroductionNeurohumoral factors play important roles in cardiac remodelling, determining the prognosis of heart failure. In particular, the sympathetic nervous system is activated in patients with chronic heart failure (CHF) [1] and sustained stimulation of the adrenergic system exerts direct adverse effects on cardiac function [2]. In spite of the importance of the adrenergic system, the effects of polymorphic mutation of adrenergic receptors on CHF remain to be fully elucidated.In the present study, we focus on the presynaptic a 2c adrenergic receptor (AR) polymorphism with the deletion of four consecutive amino acids, a 2c Del322-325, and polymorphic amino acid variants of b 1 AR, Ser49Gly and Arg389Gly. These polymorphic changes result in alteration of AR function. The presynaptic [5]. The change of b 1 AR from Arg to Gly at the 389 amino acid residue leads to the decrease in G-protein coupling [6]. Considering the importance of the adrenergic system as a modulator of cardiac remodelling, it could be proposed that polymorphisms of adrenergic receptor genes may be closely related to the risk of heart failure. Recently, Small et al. proposed that the polymorphisms of b 1 Arg389Gly and a 2c Del322-325 are synergistically related to the risk of CHF in a black population [7]. However several concerns, including the aetiology of heart failure and the absence of analysis of b 1 Ser49Gly frequency, have been raised against this study [8]. We have investigated the clinical significance of a 2c Del322-325, b 1 Ser49Gly, and b 1 Arg389Gly for the risk of heart failure due to dilated cardiomyopathy (DCM) in the Japanese. Methods SubjectsThe study subjects consisted of 91 unrelated consecutive patients with CHF due to idiopathic DCM (ma...

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs.