TY - JOUR
T1 - Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder
AU - Nunes, Abraham
AU - Stone, William
AU - Ardau, Raffaella
AU - Berghöfer, Anne
AU - Bocchetta, Alberto
AU - Chillotti, Caterina
AU - Deiana, Valeria
AU - Degenhardt, Franziska
AU - Forstner, Andreas J.
AU - Garnham, Julie S.
AU - Grof, Eva
AU - Hajek, Tomas
AU - Manchia, Mirko
AU - Mattheisen, Manuel
AU - McMahon, Francis
AU - Müller-Oerlinghausen, Bruno
AU - Nöthen, Markus M.
AU - Pinna, Marco
AU - Pisanu, Claudia
AU - O’Donovan, Claire
AU - Rietschel, Marcella D.C.
AU - Rouleau, Guy
AU - Schulze, Thomas
AU - Severino, Giovanni
AU - Slaney, Claire M.
AU - Squassina, Alessio
AU - Suwalska, Aleksandra
AU - Turecki, Gustavo
AU - Uher, Rudolf
AU - Zvolsky, Petr
AU - Cervantes, Pablo
AU - del Zompo, Maria
AU - Grof, Paul
AU - Rybakowski, Janusz
AU - Tondo, Leonardo
AU - Trappenberg, Thomas
AU - Alda, Martin
N1 - Funding Information:
Genome Canada/Genome Atlantic (M.A., A.N., R.U.), Dalhousie Department of Psychiatry Research Fund (M.A., A.N.), Dalhousie Medical Research Foundation and the Lindsay Family (M.A., A.N.), Canadian Institutes of Health Research #166098 (M.A., A.N., R.U.), Canada Research Chairs Program #231397 (R.U.), Nova Scotia Health Research Foundation Scotia Scholars Graduate Scholarship (A.N.), Killam Postgraduate Scholarship (A.N.), EMBED-BMBF-01EW1904 (MDCR).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85099256221&partnerID=8YFLogxK
U2 - 10.1038/s41398-020-01148-y
DO - 10.1038/s41398-020-01148-y
M3 - Article
C2 - 33431852
AN - SCOPUS:85099256221
SN - 2158-3188
VL - 11
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 36
ER -