Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort

Author(s):Show less -

Santoro, Marcos Leite ^{[1, 2]} ; Ota, Vanessa ^{[1, 2]} ; de Jong, Simone ^[3] ; Noto, Cristiano ^{[4, 5]} ; Spindola, Leticia M. ^{[4, 2]} ; Talarico, Fernanda ^{[4, 2]} ; Gouyea, Eduardo ^{[4, 5]} ; Lee, Sang Hyuck ^{[3, 6, 7]} ; Moretti, Patricia ^{[4, 2]} ; Curtis, Charles ^{[3, 6, 7]} ; Patel, Hamel ^{[3, 6, 7]} ; Newhouse, Stephen ^{[3, 6, 7]} ; Caryalho, Carolina Muniz ^{[4, 2]} ; Gadelha, Ary ^{[4, 2]} ; Cordeire, Quirino ^{[4, 5]} ; Bressan, Rodrigo Affonseca ^{[4, 2]} ; Belangero, Sintia Iole ^{[4, 1, 2]} ; Breen, Gerome ^{[3, 6, 7]}

Affiliation

^[1] Fed Univ Sao Paulo UNIFESP, Genet Div, Sao Paulo, SP - Brazil

^[2] Fed Univ Sao Paulo UNIFESP, Interdisciplinary Lab Clin Neurosci, Sao Paulo, SP - Brazil

^[3] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr SGDP, London - England

^[4] Fed Univ Sao Paulo UNIFESP, Dept Psychiat, Sao Paulo, SP - Brazil

^[5] Santa Casa de Misericordia sao Paulo, CAISM, Sao Paulo, SP - Brazil

^[6] South London & Maudsley NHS Trust, NIHR Maudsley Biomed Res Ctr, London SE5 8AF - England

^[7] Kings Coll London, London SE5 8AF - England

• Document type: Journal article
• Source: TRANSLATIONAL PSYCHIATRY; v. 8, AUG 31 2018.
• Web of Science Citations: 6

Abstract

In this study, we aimed to test if the schizophrenia (SCZ) polygenic risk score (PRS) was associated with clinical symptoms in (a) the first episode of psychosis pre-treatment (FEP), (b) at nine weeks after initiation of risperidone treatment (FEP-9W) and (c) with the response to risperidone. We performed a detailed clinical assessment of 60 FEP patients who were antipsychotic-naive and, again, after nine weeks of standardized treatment with risperidone. After blood collection and DNA isolation, the samples were genotyped using the Illumina PsychArrayChip and then imputed. To calculate PRS, we used the latest available GWAS summary statistics from the Psychiatric Genomics Consortium wave-2 SCZ group as a training set. We used Poisson regression to test association between PRS and clinical measurements correcting for the four principal components (genotyping). We considered a p-value < 0.0014 (Bonferroni correction) as significant. First, we verified that the schizophrenia PRS was also able to distinguish cases from controls in this south-eastern Brazilian sample, with a similar variance explained to that seen in Northern European populations. In addition, within-cases analyses, we found that PRS is significantly correlated with baseline (pre-treatment) symptoms, as measured by lower clinical global assessment of functioning (-GAF), higher depressive symptoms and higher scores on a derived excitement factor. After standardized treatment for nine weeks, the correlation with GAF and the excitement factor disappeared while depressive symptoms became negatively associated with PRS. We conclude that drug (and other treatments) may confound attempts to understand the aetiological influence on symptomatology of polygenic risk scores. These results highlight the importance of studying schizophrenia, and other disorders, pre-treatment to understand the relationship between polygenic risk and phenotypic features. (AU)

• FAPESP's process: 10/08968-6 - INVESTIGATION OF GENETIC AND EPIGENETIC MARKERS: A TRANSLATIONAL APPROACH FOR SCHIZOPHRENIA TREATMENT
• Grantee: Síntia Iole Nogueira Belangero
• Support type: Regular Research Grants
• FAPESP's process: 12/12686-1 - Potential genetic markers in early phases of schizophrenia
• Grantee: Marcos Leite Santoro
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/50830-2 - Biomarkers of treatment naive psychosis
• Grantee: Rodrigo Affonseca Bressan
• Support type: Regular Research Grants
• FAPESP's process: 16/13737-0 - Polygenic score and transcriptomic analysis in children and teenagers at risk to psychiatric disorders
• Grantee: Marcos Leite Santoro
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 16/04983-7 - Neuroimaging, genomics, transcriptomics and epigenomics: dealing with big data toward an integrative model of mental disorders
• Grantee: Jair de Jesus Mari
• Support type: Research Grants - eScience and Data Science Program - Regular Program Grants
• FAPESP's process: 11/50740-5 - Prevention in schizophrenia and bipolar disorder from neuroscience to the community: a multiphase, multimodal and translational platform for research and intervention
• Grantee: Rodrigo Affonseca Bressan
• Support type: Research Projects - Thematic Grants
• FAPESP's process: 14/07280-1 - Search for genetic markers of risk, progression and response to treatment
• Grantee: Síntia Iole Nogueira Belangero
• Support type: Regular Research Grants
• FAPESP's process: 14/22223-4 - Genome-wide expression and DNA methylation analysis in an antipsychotic-naive first episode of psychosis cohort
• Grantee: Marcos Leite Santoro
• Support type: Scholarships abroad - Research Internship - Doctorate