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

Marcos Leite Santoro; Vanessa Ota; Simone de Jong; Cristiano Noto; Leticia M. Spindola; Fernanda Talarico; Eduardo Gouvea; Sang Hyuck Lee; Patricia Moretti; Charles Curtis; Hamel Patel; Stephen Newhouse; Carolina Muniz Carvalho; Ary Gadelha; Quirino Cordeiro; Rodrigo Affonseca Bressan; Sintia Iole Belangero; Gerome Breen

doi:10.1038/s41398-018-0230-7

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

Marcos Leite Santoro, Vanessa Ota, Simone de Jong, Cristiano Noto, Leticia M. Spindola, Fernanda Talarico, Eduardo Gouvea, Sang Hyuck Lee, Patricia Moretti, Charles Curtis, Hamel Patel, Stephen Newhouse, Carolina Muniz Carvalho, Ary Gadelha, Quirino Cordeiro, Rodrigo Affonseca Bressan, Sintia Iole Belangero, Gerome Breen^*

^*Corresponding author for this work

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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.

Original language	English
Article number	174
Journal	Translational psychiatry
Volume	8
Issue number	1
Early online date	31 Aug 2018
DOIs	https://doi.org/10.1038/s41398-018-0230-7
Publication status	Published - 1 Dec 2018

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Polygenic risk score analyses_SANTORO_Accepted 14 July 2018_ GOLD VoR (CC BY)Final published version, 423 KBLicence: CC BY

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Santoro, M. L., Ota, V., de Jong, S., Noto, C., Spindola, L. M., Talarico, F., Gouvea, E., Lee, S. H., Moretti, P., Curtis, C., Patel, H., Newhouse, S., Carvalho, C. M., Gadelha, A., Cordeiro, Q., Bressan, R. A., Belangero, S. I., & Breen, G. (2018). Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort. Translational psychiatry, 8(1), Article 174. https://doi.org/10.1038/s41398-018-0230-7

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

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.",

author = "Santoro, {Marcos Leite} and Vanessa Ota and {de Jong}, Simone and Cristiano Noto and Spindola, {Leticia M.} and Fernanda Talarico and Eduardo Gouvea and Lee, {Sang Hyuck} and Patricia Moretti and Charles Curtis and Hamel Patel and Stephen Newhouse and Carvalho, {Carolina Muniz} and Ary Gadelha and Quirino Cordeiro and Bressan, {Rodrigo Affonseca} and Belangero, {Sintia Iole} and Gerome Breen",

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Santoro, ML, Ota, V, de Jong, S, Noto, C, Spindola, LM, Talarico, F, Gouvea, E, Lee, SH, Moretti, P, Curtis, C, Patel, H , Newhouse, S, Carvalho, CM, Gadelha, A, Cordeiro, Q, Bressan, RA, Belangero, SI & Breen, G 2018, 'Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort', Translational psychiatry, vol. 8, no. 1, 174. https://doi.org/10.1038/s41398-018-0230-7

TY - JOUR

T1 - Polygenic risk score analyses of symptoms and treatment response in an antipsychotic-naive first episode of psychosis cohort

AU - Santoro, Marcos Leite

AU - Ota, Vanessa

AU - de Jong, Simone

AU - Noto, Cristiano

AU - Spindola, Leticia M.

AU - Talarico, Fernanda

AU - Gouvea, Eduardo

AU - Lee, Sang Hyuck

AU - Moretti, Patricia

AU - Curtis, Charles

AU - Patel, Hamel

AU - Newhouse, Stephen

AU - Carvalho, Carolina Muniz

AU - Gadelha, Ary

AU - Cordeiro, Quirino

AU - Bressan, Rodrigo Affonseca

AU - Belangero, Sintia Iole

AU - Breen, Gerome

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41398-018-0230-7

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JO - Translational psychiatry

JF - Translational psychiatry

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ER -

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

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