Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

C Okhuijsen-Pfeifer; M Z van der Horst; C A Bousman; B Lin; K R van Eijk; S Ripke; Y Ayhan; M O Babaoglu; M Bak; W Alink; H van Beek; E Beld; A Bouhuis; M Edlinger; I M Erdogan; A Ertuğrul; G Yoca; I P Everall; T Görlitz; K P Grootens; S Gutwinski; T Hallikainen; E Jeger-Land; M de Koning; M Lähteenvuo; S E Legge; S Leucht; C Morgenroth; A Müderrisoğlu; A Narang; C Pantelis; A F Pardiñas; T Oviedo-Salcedo; J Schneider-Thoma; S Schreiter; E Repo-Tiihonen; H Tuppurainen; M Veereschild; S Veerman; M de Vos; E Wagner; D Cohen; J P A M Bogers; J T R Walters; A E Anil Yağcıoğlu; J Tiihonen; A Hasan; J J Luykx; GROUP (Genetic Risk and Outcome of Psychosis) investigators

doi:10.1038/s41398-022-01884-3

Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

C Okhuijsen-Pfeifer, M Z van der Horst, C A Bousman, B Lin, K R van Eijk, S Ripke, Y Ayhan, M O Babaoglu, M Bak, W Alink, H van Beek, E Beld, A Bouhuis, M Edlinger, I M Erdogan, A Ertuğrul, G Yoca, I P Everall, T Görlitz, K P GrootensS Gutwinski, T Hallikainen, E Jeger-Land, M de Koning, M Lähteenvuo, S E Legge, S Leucht, C Morgenroth, A Müderrisoğlu, A Narang, C Pantelis, A F Pardiñas, T Oviedo-Salcedo, J Schneider-Thoma, S Schreiter, E Repo-Tiihonen, H Tuppurainen, M Veereschild, S Veerman, M de Vos, E Wagner, D Cohen, J P A M Bogers, J T R Walters, A E Anil Yağcıoğlu, J Tiihonen, A Hasan, J J Luykx^*, GROUP (Genetic Risk and Outcome of Psychosis) investigators

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

Original language	English
Article number	145
Number of pages	9
Journal	Translational Psychiatry
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41398-022-01884-3
Publication status	Published - 7 Apr 2022

Keywords

Antipsychotic Agents/therapeutic use
Clozapine/therapeutic use
Cytochrome P-450 CYP1A2/genetics
Cytochrome P-450 CYP2C19/genetics
Cytochrome P-450 CYP2D6/genetics
Genome-Wide Association Study
Humans
Schizophrenia/chemically induced
CYTOCHROME-P450
CYP2C19
IDENTIFICATION
POLYGENIC RISK SCORE
PHARMACOLOGICAL-TREATMENT
POLYMORPHISMS
GENETIC RISK
N-DESMETHYLCLOZAPINE
PHARMACOGENETICS
BRAIN

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Okhuijsen-Pfeifer, C., van der Horst, M. Z., Bousman, C. A., Lin, B., van Eijk, K. R., Ripke, S., Ayhan, Y., Babaoglu, M. O., Bak, M., Alink, W., van Beek, H., Beld, E., Bouhuis, A., Edlinger, M., Erdogan, I. M., Ertuğrul, A., Yoca, G., Everall, I. P., Görlitz, T., ... GROUP (Genetic Risk and Outcome of Psychosis) investigators (2022). Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders. Translational Psychiatry, 12(1), Article 145. https://doi.org/10.1038/s41398-022-01884-3

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title = "Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders",

abstract = "Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.",

keywords = "Antipsychotic Agents/therapeutic use, Clozapine/therapeutic use, Cytochrome P-450 CYP1A2/genetics, Cytochrome P-450 CYP2C19/genetics, Cytochrome P-450 CYP2D6/genetics, Genome-Wide Association Study, Humans, Schizophrenia/chemically induced, CYTOCHROME-P450, CYP2C19, IDENTIFICATION, POLYGENIC RISK SCORE, PHARMACOLOGICAL-TREATMENT, POLYMORPHISMS, GENETIC RISK, N-DESMETHYLCLOZAPINE, PHARMACOGENETICS, BRAIN",

author = "C Okhuijsen-Pfeifer and {van der Horst}, {M Z} and Bousman, {C A} and B Lin and {van Eijk}, {K R} and S Ripke and Y Ayhan and Babaoglu, {M O} and M Bak and W Alink and {van Beek}, H and E Beld and A Bouhuis and M Edlinger and Erdogan, {I M} and A Ertuğrul and G Yoca and Everall, {I P} and T G{\"o}rlitz and Grootens, {K P} and S Gutwinski and T Hallikainen and E Jeger-Land and {de Koning}, M and M L{\"a}hteenvuo and Legge, {S E} and S Leucht and C Morgenroth and A M{\"u}derrisoğlu and A Narang and C Pantelis and Pardi{\~n}as, {A F} and T Oviedo-Salcedo and J Schneider-Thoma and S Schreiter and E Repo-Tiihonen and H Tuppurainen and M Veereschild and S Veerman and {de Vos}, M and E Wagner and D Cohen and Bogers, {J P A M} and Walters, {J T R} and Yağcıoğlu, {A E Anil} and J Tiihonen and A Hasan and Luykx, {J J} and {GROUP (Genetic Risk and Outcome of Psychosis) investigators}",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = apr,

day = "7",

doi = "10.1038/s41398-022-01884-3",

language = "English",

volume = "12",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Okhuijsen-Pfeifer, C, van der Horst, MZ, Bousman, CA, Lin, B, van Eijk, KR, Ripke, S, Ayhan, Y, Babaoglu, MO, Bak, M, Alink, W, van Beek, H, Beld, E, Bouhuis, A, Edlinger, M, Erdogan, IM, Ertuğrul, A, Yoca, G, Everall, IP, Görlitz, T, Grootens, KP, Gutwinski, S, Hallikainen, T, Jeger-Land, E, de Koning, M, Lähteenvuo, M, Legge, SE, Leucht, S, Morgenroth, C, Müderrisoğlu, A, Narang, A, Pantelis, C, Pardiñas, AF, Oviedo-Salcedo, T, Schneider-Thoma, J, Schreiter, S, Repo-Tiihonen, E, Tuppurainen, H, Veereschild, M, Veerman, S, de Vos, M, Wagner, E, Cohen, D, Bogers, JPAM, Walters, JTR, Yağcıoğlu, AEA, Tiihonen, J, Hasan, A, Luykx, JJ & GROUP (Genetic Risk and Outcome of Psychosis) investigators 2022, 'Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders', Translational Psychiatry, vol. 12, no. 1, 145. https://doi.org/10.1038/s41398-022-01884-3

TY - JOUR

T1 - Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

AU - Okhuijsen-Pfeifer, C

AU - van der Horst, M Z

AU - Bousman, C A

AU - Lin, B

AU - van Eijk, K R

AU - Ripke, S

AU - Ayhan, Y

AU - Babaoglu, M O

AU - Bak, M

AU - Alink, W

AU - van Beek, H

AU - Beld, E

AU - Bouhuis, A

AU - Edlinger, M

AU - Erdogan, I M

AU - Ertuğrul, A

AU - Yoca, G

AU - Everall, I P

AU - Görlitz, T

AU - Grootens, K P

AU - Gutwinski, S

AU - Hallikainen, T

AU - Jeger-Land, E

AU - de Koning, M

AU - Lähteenvuo, M

AU - Legge, S E

AU - Leucht, S

AU - Morgenroth, C

AU - Müderrisoğlu, A

AU - Narang, A

AU - Pantelis, C

AU - Pardiñas, A F

AU - Oviedo-Salcedo, T

AU - Schneider-Thoma, J

AU - Schreiter, S

AU - Repo-Tiihonen, E

AU - Tuppurainen, H

AU - Veereschild, M

AU - Veerman, S

AU - de Vos, M

AU - Wagner, E

AU - Cohen, D

AU - Bogers, J P A M

AU - Walters, J T R

AU - Yağcıoğlu, A E Anil

AU - Tiihonen, J

AU - Hasan, A

AU - Luykx, J J

AU - GROUP (Genetic Risk and Outcome of Psychosis) investigators

PY - 2022/4/7

Y1 - 2022/4/7

N2 - Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

AB - Clozapine is the most effective antipsychotic for patients with treatment-resistant schizophrenia. However, response is highly variable and possible genetic underpinnings of this variability remain unknown. Here, we performed polygenic risk score (PRS) analyses to estimate the amount of variance in symptom severity among clozapine-treated patients explained by PRSs (R2) and examined the association between symptom severity and genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activity. Genome-wide association (GWA) analyses were performed to explore loci associated with symptom severity. A multicenter cohort of 804 patients (after quality control N = 684) with schizophrenia spectrum disorder treated with clozapine were cross-sectionally assessed using the Positive and Negative Syndrome Scale and/or the Clinical Global Impression-Severity (CGI-S) scale. GWA and PRS regression analyses were conducted. Genotype-predicted CYP1A2, CYP2D6, and CYP2C19 enzyme activities were calculated. Schizophrenia-PRS was most significantly and positively associated with low symptom severity (p = 1.03 × 10-3; R2 = 1.85). Cross-disorder-PRS was also positively associated with lower CGI-S score (p = 0.01; R2 = 0.81). Compared to the lowest tertile, patients in the highest schizophrenia-PRS tertile had 1.94 times (p = 6.84×10-4) increased probability of low symptom severity. Higher genotype-predicted CYP2C19 enzyme activity was independently associated with lower symptom severity (p = 8.44×10-3). While no locus surpassed the genome-wide significance threshold, rs1923778 within NFIB showed a suggestive association (p = 3.78×10-7) with symptom severity. We show that high schizophrenia-PRS and genotype-predicted CYP2C19 enzyme activity are independently associated with lower symptom severity among individuals treated with clozapine. Our findings open avenues for future pharmacogenomic projects investigating the potential of PRS and genotype-predicted CYP-activity in schizophrenia.

KW - Antipsychotic Agents/therapeutic use

KW - Clozapine/therapeutic use

KW - Cytochrome P-450 CYP1A2/genetics

KW - Cytochrome P-450 CYP2C19/genetics

KW - Cytochrome P-450 CYP2D6/genetics

KW - Genome-Wide Association Study

KW - Humans

KW - Schizophrenia/chemically induced

KW - CYTOCHROME-P450

KW - CYP2C19

KW - IDENTIFICATION

KW - POLYGENIC RISK SCORE

KW - PHARMACOLOGICAL-TREATMENT

KW - POLYMORPHISMS

KW - GENETIC RISK

KW - N-DESMETHYLCLOZAPINE

KW - PHARMACOGENETICS

KW - BRAIN

U2 - 10.1038/s41398-022-01884-3

DO - 10.1038/s41398-022-01884-3

M3 - Article

C2 - 35393395

SN - 2158-3188

VL - 12

JO - Translational Psychiatry

JF - Translational Psychiatry

IS - 1

M1 - 145

ER -