TY - JOUR
T1 - Identifying the genetic risk factors for treatment response to lurasidone by genome-wide association study
T2 - A meta-analysis of samples from three independent clinical trials
AU - Li, Jiang
AU - Loebel, Antony
AU - Meltzer, Herbert Y.
N1 - Funding Information:
This study was supported by Sunovion Pharmaceuticals Inc. by a grant (No. SP0040239) to Northwestern University School of Medicine. This research is also supported by donations from the Weisman Foundation.
Funding Information:
JL has no conflicts of interest. AL is an employee of Sunovion Pharmaceutical Inc. HYM is a stockholder in SureGene and ACADIA and receives additional grant support from Sunovion and Sumitomo Dainippon Pharma for other studies. HYM also receives grant support from Alkermes, Auspex, Boehringer Mannheim, Eli Lilly, Janssen, Lundbeck, Mag T, Otsuka and Reviva.
Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
KW - Antipsychotic
KW - Lurasidone
KW - Pharmacogenomics
KW - Polygenic risk
KW - Schizophrenia
KW - Synaptic adhesion
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U2 - 10.1016/j.schres.2018.04.006
DO - 10.1016/j.schres.2018.04.006
M3 - Article
C2 - 29730043
AN - SCOPUS:85046708493
SN - 0920-9964
VL - 199
SP - 203
EP - 213
JO - Schizophrenia Research
JF - Schizophrenia Research
ER -
