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

Jiang Li, Antony Loebel, Herbert Y. Meltzer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 K 2P 9.1 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.

Original languageEnglish (US)
Pages (from-to)203-213
Number of pages11
JournalSchizophrenia Research
Volume199
DOIs
StatePublished - Sep 2018

Keywords

  • Antipsychotic
  • Lurasidone
  • Pharmacogenomics
  • Polygenic risk
  • Schizophrenia
  • Synaptic adhesion

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

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