Identifying the genetic risk factors for treatment response to lurasidone by genome-wide association study: A meta-analysis of samples from three independent clinical trials

Schizophr Res. 2018 Sep:199:203-213. doi: 10.1016/j.schres.2018.04.006. Epub 2018 May 2.

Abstract

A genome-wide association study (GWAS) of response of schizophrenia patients to the atypical antipsychotic drug, lurasidone, based on two double-blind registration trials, identified SNPs from four classes of genes as predictors of efficacy, but none were genome wide significant (GWS). After inclusion of data from a third lurasidone trial, meta-analysis identified a GWS marker and other findings consistent with our first study. The primary end-point was change in Total Positive and Negative Syndrome Scale (PANSS) between baseline and last observation carried forward. rs4736253, a genetic locus near KCNK9, encoding the K2P9.1 potassium channel, with a role in cognition and neurodevelopment, was the top marker in patients of European ancestry (EUR) (n = 264), reaching GWS (p = 4.78 × 10-8). rs10180106 (p = 4.92 × 10-7), located at an intron region of CTNNA2, a SCZ risk gene important for dendritic spine stabilization, was one of other best response markers for EUR patients. SNPs at STXBP5L (rs511841, p = 2.63 × 10-7) were the top markers for patients of African ancestry (n = 158). The association between PTPRD, NRG1, and MAGI1 previously reported to be related to response to lurasidone in the first two trials, showed a trend of significant association in the third trial. None of these genetic loci showed significant associations with clinical response in the corresponding placebo groups (n = 107 for EUR; n = 58 for AFR). This meta-analysis yielded the first GWAS-based GWS biomarker for lurasidone response and additional support for the conclusion that genes related to synaptic biology and/or risk for SCZ are the strongest predictors of response to lurasidone in schizophrenia patients.

Keywords: Antipsychotic; Lurasidone; Pharmacogenomics; Polygenic risk; Schizophrenia; Synaptic adhesion.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / adverse effects*
  • Antipsychotic Agents / therapeutic use*
  • Black People / genetics
  • Genome-Wide Association Study
  • Humans
  • Lurasidone Hydrochloride / adverse effects*
  • Lurasidone Hydrochloride / therapeutic use*
  • Multicenter Studies as Topic
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Randomized Controlled Trials as Topic
  • Risk Factors
  • Schizophrenia / drug therapy*
  • Schizophrenia / genetics*
  • White People / genetics

Substances

  • Antipsychotic Agents
  • Lurasidone Hydrochloride