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Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
A. Nunes, W. Stone, R. Ardau, A. Berghöfer, A. Bocchetta, C. Chillotti, V. Deiana, F. Degenhardt, AJ. Forstner, JS. Garnham, E. Grof, T. Hajek, M. Manchia, M. Mattheisen, F. McMahon, B. Müller-Oerlinghausen, MM. Nöthen, M. Pinna, C. Pisanu, C....
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
166098
Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) - International
166098
Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) - International
231397
Canada Research Chairs (Chaires de recherche du Canada) - International
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- MeSH
- Antimanic Agents therapeutic use MeSH
- Bipolar Disorder * drug therapy genetics MeSH
- Phenotype MeSH
- Humans MeSH
- Lithium therapeutic use MeSH
- Lithium Compounds therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Centre for Human Genetics University of Marburg Marburg Germany
Centro Lucio Bini Cagliari e Roma Cagliari Italy
Charité Universitätsmedizin Berlin Berlin Germany
Department of Adult Psychiatry Poznan University of Medical Sciences Poznan Poland
Department of Biomedicine University of Basel Basel Switzerland
Department of Mental Health Poznan University of Medical Sciences Poznan Poland
Department of Pharmacology Dalhousie University Halifax Nova Scotia Canada
Department of Psychiatric Nursing Poznan University of Medical Sciences Poznan Poland
Department of Psychiatry Charles University Prague Czech Republic
Department of Psychiatry Dalhousie University Halifax NS Canada
Department of Psychiatry McGill University Health Centre Montreal Québec Canada
Department of Psychiatry University of Toronto Toronto Ontario Canada
Department of Psychiatry University of Wurzburg Wurzburg Germany
Faculty of Computer Science Dalhousie University Halifax NS Canada
Harvard Medical School and McLean Hospital Boston MA USA
Institute of Psychiatric Phenomics and Genomics Munich Germany
Montreal Neurological Institute McGill University Montreal QC Canada
Mood Disorders Center of Ottawa Ottawa Ontario Canada
References provided by Crossref.org
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