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.

Details

Title
Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders
Author
Okhuijsen-Pfeifer, C 1   VIAFID ORCID Logo  ; van der Horst M Z 2   VIAFID ORCID Logo  ; Bousman, C A 3   VIAFID ORCID Logo  ; Lin, B 1 ; van Eijk K R 4 ; Ripke, S 5 ; Ayhan, Y 6 ; Babaoglu, M O 7 ; Bak, M 8 ; Alink, W 9 ; van Beek H 10 ; Beld, E 11 ; Bouhuis, A 12 ; Edlinger, M 13 ; Erdogan, I M 6   VIAFID ORCID Logo  ; Ertuğrul, A 6 ; Yoca, G 14 ; Everall, I P 15 ; Görlitz, T 16 ; van Amelsvoort T 17 ; Bartels-Velthuis, A A 18 ; Bruggeman, R 19 ; Cahn, W 20 ; Guloksuz, S 21 ; de, Haan L 22 ; Kahn, R S 23 ; Schirmbeck, F 22 ; Simons C J P 18 ; van Os J 20 ; Alizadeh, B Z 24 ; Luykx, J J 2 ; Rutten B P F 18 ; van Winkel R 25 ; Grootens, K P 26 ; Gutwinski, S 5 ; Hallikainen, T 27 ; Jeger-Land, E 28 ; de, Koning M 22 ; Lähteenvuo, M 27   VIAFID ORCID Logo  ; Legge, S E 29   VIAFID ORCID Logo  ; Leucht, S 30 ; Morgenroth, C 5 ; Müderrisoğlu, A 31 ; Narang, A 32 ; Pantelis, C 33   VIAFID ORCID Logo  ; Pardiñas, A F 29   VIAFID ORCID Logo  ; Oviedo-Salcedo, T 34 ; Schneider-Thoma, J 30 ; Schreiter, S 35 ; Repo-Tiihonen, E 27 ; Tuppurainen, H 27 ; Veereschild, M 36 ; Veerman, S 37 ; de, Vos M 36 ; Wagner, E 34   VIAFID ORCID Logo  ; Cohen, D 38 ; Bogers J P A M 39   VIAFID ORCID Logo  ; Walters, J T, R 29 ; Anil, Yağcıoğlu A E 6 ; Tiihonen, J 40   VIAFID ORCID Logo  ; Hasan, A 16 

1  University Medical Center Utrecht, Utrecht University, Brain Center, Department of Psychiatry, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); University Medical Center Utrecht, Utrecht University, Brain Center, Department of Translational Neuroscience, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234) 
2  University Medical Center Utrecht, Utrecht University, Brain Center, Department of Psychiatry, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); University Medical Center Utrecht, Utrecht University, Brain Center, Department of Translational Neuroscience, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); GGNet Mental Health, Warnsveld, The Netherlands (GRID:grid.491146.f) (ISNI:0000 0004 0478 3153) 
3  University of Calgary, Department of Medical Genetics, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697); University of Calgary, Department of Psychiatry, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697); University of Calgary, Department of Physiology & Pharmacology, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697); University of Melbourne, Melbourne Neuropsychiatry Centre, Department of Psychiatry, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
4  University Medical Center Utrecht, Utrecht University, Brain Center, Department of Translational Neuroscience, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234) 
5  Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639) 
6  Hacettepe University, Department of Psychiatry, Faculty of Medicine, Ankara, Turkey (GRID:grid.14442.37) (ISNI:0000 0001 2342 7339) 
7  Hacettepe University, Department of Pharmacology, Faculty of Medicine, Ankara, Turkey (GRID:grid.14442.37) (ISNI:0000 0001 2342 7339) 
8  Maastricht University, Department of Psychiatry and Neuropsychology, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099); Mondriaan, Mental Health Institute, Maastricht, The Netherlands (GRID:grid.491353.9) (ISNI:0000 0004 0466 0217) 
9  Pro Persona, Multicomplexe Zorg, Wolfheze, The Netherlands (GRID:grid.491369.0) (ISNI:0000 0004 0466 1666) 
10  Mental Health Services Rivierduinen, Clinical Recovery Clinic, Leiden, The Netherlands (GRID:grid.491369.0) 
11  Mental Health Organization North‐Holland North location Den Helder, Den Helder, The Netherlands (GRID:grid.491369.0) 
12  Pro Persona Mental Healthcare, Program for early psychosis & severe mental illness, Wolfheze, The Netherlands (GRID:grid.491369.0) (ISNI:0000 0004 0466 1666) 
13  Medical University Innsbruck, Department of Psychiatry, Psychotherapy and Psychosomatics, Division for Psychiatry I, Innsbruck, Austria (GRID:grid.5361.1) (ISNI:0000 0000 8853 2677) 
14  Hacettepe University, Department of Psychiatry, Faculty of Medicine, Ankara, Turkey (GRID:grid.14442.37) (ISNI:0000 0001 2342 7339); Ministry of Health, Şarkışla State Hospital, Sivas, Turkey (GRID:grid.415700.7) (ISNI:0000 0004 0643 0095) 
15  University of Melbourne, Melbourne Neuropsychiatry Centre, Department of Psychiatry, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); King’s College London, Institute of Psychiatry, Psychology and Neuroscience, London, United Kingdom (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
16  University Hospital, LMU Munich, Department of Psychiatry and Psychotherapy, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X); Medical Faculty University Augsburg, Bezirkskrankenhaus Augsburg, Department of Psychiatry, Psychotherapy and Psychosomatics, Augsburg, Germany (GRID:grid.500075.7) (ISNI:0000 0001 0409 5412) 
17  University of Montreal, Department of Pediatrics, Montreal, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2292 3357) 
18  Maastricht University, Department of Psychiatry and Neuropsychology, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099) 
19  University of Groningen, Department of Clinical and Developmental Neuropsychology, Groningen, Netherlands (GRID:grid.4830.f) (ISNI:0000 0004 0407 1981) 
20  University Medical Center Utrecht, Utrecht University, Brain Center, Department of Psychiatry, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234) 
21  Maastricht University, Department of Psychiatry and Neuropsychology, Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099); Yale University, Department of Psychiatry, School of Medicine, New Haven, United States (GRID:grid.47100.32) (ISNI:0000000419368710) 
22  Arkin, Institute for Mental Health, Amsterdam, The Netherlands (GRID:grid.491093.6) (ISNI:0000 0004 0378 2028); Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
23  University Medical Center Utrecht, Utrecht University, Brain Center, Department of Psychiatry, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000000120346234); Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, United States (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
24  University of Groningen, University Medical Center Groningen, Department of Radiation Oncology, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598); University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
25  Center for Clinical Psychiatry, Department of Neuroscience, Research Group Psychiatry, Leuven, Belgium (GRID:grid.5012.6) 
26  Reinier van Arkel, s-Hertogenbosch, The Netherlands (GRID:grid.491422.8) (ISNI:0000 0004 0546 0823); Radboud University Medical Centre, Unit for Clinical Psychopharmacology and Neuropsychiatry, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
27  University of Kuopio, Niuvanniemi Hospital, Department of Forensic Psychiatry, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490) 
28  Arkin, Institute for Mental Health, Amsterdam, The Netherlands (GRID:grid.491093.6) (ISNI:0000 0004 0378 2028) 
29  Cardiff University, Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff, United Kingdom (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
30  Technical University of Munich, Department of Psychiatry and Psychotherapy, School of Medicine, Klinikum rechts der Isar, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
31  Kırıkkale University, Department of Pharmacology, Faculty of Medicine, Kırıkkale, Turkey (GRID:grid.411047.7) (ISNI:0000 0004 0595 9528) 
32  University of Calgary, Department of Medical Genetics, Calgary, Canada (GRID:grid.22072.35) (ISNI:0000 0004 1936 7697) 
33  University of Melbourne, Melbourne Neuropsychiatry Centre, Department of Psychiatry, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
34  University Hospital, LMU Munich, Department of Psychiatry and Psychotherapy, Munich, Germany (GRID:grid.5252.0) (ISNI:0000 0004 1936 973X) 
35  Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Psychiatry and Psychotherapy, Berlin, Germany (GRID:grid.7468.d) (ISNI:0000 0001 2248 7639); BIH Biomedical Innovation Academy, Berlin Institute of Health (BIH), Berlin, Germany (GRID:grid.484013.a) (ISNI:0000 0004 6879 971X) 
36  GGNet Mental Health, Warnsveld, The Netherlands (GRID:grid.491146.f) (ISNI:0000 0004 0478 3153) 
37  Mental Health Organization North‐Holland North location Alkmaar, Alkmaar, The Netherlands (GRID:grid.491146.f) 
38  Mental Health Organization North‐Holland North location Heerhugowaard, Heerhugowaard, The Netherlands (GRID:grid.5252.0) 
39  Mental Health Services Rivierduinen, High Care Clinics, Leiden, The Netherlands (GRID:grid.5252.0) 
40  University of Kuopio, Niuvanniemi Hospital, Department of Forensic Psychiatry, Kuopio, Finland (GRID:grid.9668.1) (ISNI:0000 0001 0726 2490); Karolinska Institutet, Department of Clinical Neuroscience, Solna, Sweden (GRID:grid.465198.7); Stockholm City Council, Center for Psychiatric Research, Stockholm, Sweden (GRID:grid.465198.7) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
21583188
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41398-022-01884-3
ProQuest document ID
2647959731
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.