TY - JOUR
T1 - Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis
AU - Zhang, Jian Ping
AU - Robinson, Delbert
AU - Yu, Jin
AU - Gallego, Juan
AU - Fleischhacker, W. Wolfgang
AU - Kahn, Rene S.
AU - Crespo-Facorro, Benedicto
AU - Vazquez-Bourgon, Javier
AU - Kane, John M.
AU - Malhotra, Anil K.
AU - Lencz, Todd
N1 - Funding Information:
Dr. Zhang has received grant support from the Brain and Behavioral Research Foundation, Genomind, and NIMH. Dr. Robinson has served as a consultant to Asubio, Costello Medical Consulting, Innovative Science Solutions, Janssen, Neurocrine, Otsuka, and Shire; and he has received research support from Otsuka. Dr. Fleischhacker has received grant support from AstraZeneca, Boehringer-Ingelheim, Janssen, Lundbeck, Otsuka, Pfizer, and Sanofi; he has served on advisory panels for Boehringer-Ingelheim, Dainippon Sumitomo Pharma, Janssen, Lundbeck, Otsuka, Richter Gedeon, and Teva; and he has received speaker’s honoraria from Janssen, Lundbeck, Otsuka, and Recordati. Dr. Kahn has received honoraria from Alkermes, Gedeon Richter, Janssen-Cilag, Lundbeck, and Minerva Neuroscience. Dr. Crespo-Facorro has received research support from the Ministerio de Ciencia e Innovación, Madrid; he has received speaker’s honoraria from Johnson and Johnson, Lundbeck, and Otsuka; and he has served as an advisor or consultant to and received honoraria from Alkermes, Casen Recordati, Lundbeck, Otsuka, and Teva. Dr. Kane has served as a consultant to or received honoraria from Alkermes, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest (Allergan), Genentech, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceutica, Johnson and Johnson, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda, and Teva; he has received grant support from Janssen and Otsuka; he has served on advisory boards for Alkermes, Intracellular Therapies, Lundbeck, Neurocrine, Otsuka, Pierre Fabre, Takeda, and Teva; and he is a shareholder with LB Pharmaceuticals, MedAvante, and Vanguard Research Group. Dr. Malhotra has received grant support from NIMH and has served as a consultant to Concert Pharma and Genomind and on the advisory board for InformedDNA. Dr. Lencz has served as a consultant to Genomind and has received grant support from the Brain and Behavioral Research Foundation, NIMH, and the U.S.-Israel Binational Science Foundation. The other authors report no financial relationships with commercial interests.
Funding Information:
Supported in part by NIH (grant K23MH097108 to Dr. Zhang, grant R21MH099868 to Dr. Lencz, grant P30MH090590 to Dr. Kane, and grant P50MH080173 to Dr. Malhotra) and by NARSAD Young Investigator grants from the Brain and Behavior Research Foundation (to Dr. Zhang).
Publisher Copyright:
© 2019 American Journal of Psychiatry.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - OBJECTIVE: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510).METHOD: All study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout.RESULTS: In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples).CONCLUSIONS: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.
AB - OBJECTIVE: Pharmacogenomic studies of antipsychotics have typically examined effects of individual polymorphisms. By contrast, polygenic risk scores (PRSs) derived from genome-wide association studies (GWAS) can quantify the influence of thousands of common alleles of small effect in a single measure. The authors examined whether PRSs for schizophrenia were predictive of antipsychotic efficacy in four independent cohorts of patients with first-episode psychosis (total N=510).METHOD: All study subjects received initial treatment with antipsychotic medication for first-episode psychosis, and all were genotyped on standard single-nucleotide polymorphism (SNP) arrays imputed to the 1000 Genomes Project reference panel. PRS was computed based on the results of the large-scale schizophrenia GWAS reported by the Psychiatric Genomics Consortium. Symptoms were measured by using total symptom rating scales at baseline and at week 12 or at the last follow-up visit before dropout.RESULTS: In the discovery cohort, higher PRS significantly predicted higher symptom scores at the 12-week follow-up (controlling for baseline symptoms, sex, age, and ethnicity). The PRS threshold set at a p value <0.01 gave the strongest result in the discovery cohort and was used to replicate the findings in the other three cohorts. Higher PRS significantly predicted greater posttreatment symptoms in the combined replication analysis and was individually significant in two of the three replication cohorts. Across the four cohorts, PRS was significantly predictive of adjusted 12-week symptom scores (pooled partial r=0.18; 3.24% of variance explained). Patients with low PRS were more likely to be treatment responders than patients with high PRS (odds ratio=1.91 in the two Caucasian samples).CONCLUSIONS: Patients with higher PRS for schizophrenia tended to have less improvement with antipsychotic drug treatment. PRS burden may have potential utility as a prognostic biomarker.
KW - Adult
KW - Antipsychotic Agents/therapeutic use
KW - Episode of Care
KW - Female
KW - Genome-Wide Association Study
KW - Humans
KW - Male
KW - Multifactorial Inheritance
KW - Predictive Value of Tests
KW - Prognosis
KW - Psychopathology
KW - Psychotic Disorders/diagnosis
KW - Risk Assessment/methods
KW - Schizophrenia/diagnosis
KW - Schizophrenic Psychology
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85059343232&partnerID=8YFLogxK
U2 - 10.1176/appi.ajp.2018.17121363
DO - 10.1176/appi.ajp.2018.17121363
M3 - Article
C2 - 30392411
AN - SCOPUS:85059343232
SN - 0002-953X
VL - 176
SP - 21
EP - 28
JO - American Journal of Psychiatry
JF - American Journal of Psychiatry
IS - 1
ER -