Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
Abstract Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-r...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-020-01148-y |
| _version_ | 1831522867859161088 |
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| author | Abraham Nunes William Stone Raffaella Ardau Anne Berghöfer Alberto Bocchetta Caterina Chillotti Valeria Deiana Franziska Degenhardt Andreas J. Forstner Julie S. Garnham Eva Grof Tomas Hajek Mirko Manchia Manuel Mattheisen Francis McMahon Bruno Müller-Oerlinghausen Markus M. Nöthen Marco Pinna Claudia Pisanu Claire O’Donovan Marcella D. C. Rietschel Guy Rouleau Thomas Schulze Giovanni Severino Claire M. Slaney Alessio Squassina Aleksandra Suwalska Gustavo Turecki Rudolf Uher Petr Zvolsky Pablo Cervantes Maria del Zompo Paul Grof Janusz Rybakowski Leonardo Tondo Thomas Trappenberg Martin Alda |
| author_facet | Abraham Nunes William Stone Raffaella Ardau Anne Berghöfer Alberto Bocchetta Caterina Chillotti Valeria Deiana Franziska Degenhardt Andreas J. Forstner Julie S. Garnham Eva Grof Tomas Hajek Mirko Manchia Manuel Mattheisen Francis McMahon Bruno Müller-Oerlinghausen Markus M. Nöthen Marco Pinna Claudia Pisanu Claire O’Donovan Marcella D. C. Rietschel Guy Rouleau Thomas Schulze Giovanni Severino Claire M. Slaney Alessio Squassina Aleksandra Suwalska Gustavo Turecki Rudolf Uher Petr Zvolsky Pablo Cervantes Maria del Zompo Paul Grof Janusz Rybakowski Leonardo Tondo Thomas Trappenberg Martin Alda |
| author_sort | Abraham Nunes |
| collection | DOAJ |
| description | Abstract Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers. |
| first_indexed | 2024-12-14T03:01:01Z |
| format | Article |
| id | doaj.art-148507cd1abd48b0b4092cfa43da61f1 |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-14T03:01:01Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-148507cd1abd48b0b4092cfa43da61f12022-12-21T23:19:31ZengNature Publishing GroupTranslational Psychiatry2158-31882021-01-0111111310.1038/s41398-020-01148-yExemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorderAbraham Nunes0William Stone1Raffaella Ardau2Anne Berghöfer3Alberto Bocchetta4Caterina Chillotti5Valeria Deiana6Franziska Degenhardt7Andreas J. Forstner8Julie S. Garnham9Eva Grof10Tomas Hajek11Mirko Manchia12Manuel Mattheisen13Francis McMahon14Bruno Müller-Oerlinghausen15Markus M. Nöthen16Marco Pinna17Claudia Pisanu18Claire O’Donovan19Marcella D. C. Rietschel20Guy Rouleau21Thomas Schulze22Giovanni Severino23Claire M. Slaney24Alessio Squassina25Aleksandra Suwalska26Gustavo Turecki27Rudolf Uher28Petr Zvolsky29Pablo Cervantes30Maria del Zompo31Paul Grof32Janusz Rybakowski33Leonardo Tondo34Thomas Trappenberg35Martin Alda36Department of Psychiatry, Dalhousie UniversityFaculty of Computer Science, Dalhousie UniversityUnit of Clinical Pharmacology & San Giovanni di Dio Hospital, University Hospital of CagliariCharité University Medical Center, Campus Charité Mitte, Institute for Social Medicine, Epidemiology and Health EconomicsUnit of Clinical Pharmacology & San Giovanni di Dio Hospital, University Hospital of CagliariUnit of Clinical Pharmacology & San Giovanni di Dio Hospital, University Hospital of CagliariDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of CagliariInstitute of Human Genetics, University of Bonn, School of Medicine & University Hospital BonnInstitute of Human Genetics, University of Bonn, School of Medicine & University Hospital BonnDepartment of Psychiatry, Dalhousie UniversityMood Disorders Center of OttawaDepartment of Psychiatry, Dalhousie UniversityDepartment of Medical Sciences and Public Health, Section of Psychiatry, University of CagliariDepartment of Psychiatry, University of WurzburgNational Institute of Mental HealthCharité Universitätsmedizin-BerlinInstitute of Human Genetics, University of Bonn, School of Medicine & University Hospital BonnCentro Lucio Bini, Cagliari e RomaDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of CagliariDepartment of Psychiatry, Dalhousie UniversityCentral Institute of Mental Health, Medical Faculty Mannheim, Heidelberg UniversityMontreal Neurological Institute, McGill UniversityInstitute of Psychiatric Phenomics and GenomicsDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of CagliariDepartment of Psychiatry, Dalhousie UniversityDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of CagliariDepartment of Adult Psychiatry, Poznan University of Medical SciencesDepartment of Psychiatry, McGill University Health CentreDepartment of Psychiatry, Dalhousie UniversityDepartment of Psychiatry, Charles UniversityDepartment of Psychiatry, McGill University Health CentreDepartment of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of CagliariMood Disorders Center of OttawaDepartment of Adult Psychiatry, Poznan University of Medical SciencesCentro Lucio Bini, Cagliari e RomaFaculty of Computer Science, Dalhousie UniversityDepartment of Psychiatry, Dalhousie UniversityAbstract Predicting lithium response (LiR) in bipolar disorder (BD) may inform treatment planning, but phenotypic heterogeneity complicates discovery of genomic markers. We hypothesized that patients with “exemplary phenotypes”—those whose clinical features are reliably associated with LiR and non-response (LiNR)—are more genetically separable than those with less exemplary phenotypes. Using clinical data collected from people with BD (n = 1266 across 7 centers; 34.7% responders), we computed a “clinical exemplar score,” which measures the degree to which a subject’s clinical phenotype is reliably predictive of LiR/LiNR. For patients whose genotypes were available (n = 321), we evaluated whether a subgroup of responders/non-responders with the top 25% of clinical exemplar scores (the “best clinical exemplars”) were more accurately classified based on genetic data, compared to a subgroup with the lowest 25% of clinical exemplar scores (the “poor clinical exemplars”). On average, the best clinical exemplars of LiR had a later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best clinical exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p = 0.0032) among poor clinical exemplars. Variants in the Alzheimer’s amyloid–secretase pathway, along with G-protein-coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were informative predictors. This study must be replicated on larger samples and extended to predict response to other mood stabilizers.https://doi.org/10.1038/s41398-020-01148-y |
| spellingShingle | Abraham Nunes William Stone Raffaella Ardau Anne Berghöfer Alberto Bocchetta Caterina Chillotti Valeria Deiana Franziska Degenhardt Andreas J. Forstner Julie S. Garnham Eva Grof Tomas Hajek Mirko Manchia Manuel Mattheisen Francis McMahon Bruno Müller-Oerlinghausen Markus M. Nöthen Marco Pinna Claudia Pisanu Claire O’Donovan Marcella D. C. Rietschel Guy Rouleau Thomas Schulze Giovanni Severino Claire M. Slaney Alessio Squassina Aleksandra Suwalska Gustavo Turecki Rudolf Uher Petr Zvolsky Pablo Cervantes Maria del Zompo Paul Grof Janusz Rybakowski Leonardo Tondo Thomas Trappenberg Martin Alda Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder Translational Psychiatry |
| title | Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| title_full | Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| title_fullStr | Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| title_full_unstemmed | Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| title_short | Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| title_sort | exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder |
| url | https://doi.org/10.1038/s41398-020-01148-y |
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