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...
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Gespeichert in:
| Autor*in: |
Abraham Nunes [verfasserIn] William Stone [verfasserIn] Raffaella Ardau [verfasserIn] Anne Berghöfer [verfasserIn] Alberto Bocchetta [verfasserIn] Caterina Chillotti [verfasserIn] Valeria Deiana [verfasserIn] Franziska Degenhardt [verfasserIn] Andreas J. Forstner [verfasserIn] Julie S. Garnham [verfasserIn] Eva Grof [verfasserIn] Tomas Hajek [verfasserIn] Mirko Manchia [verfasserIn] Manuel Mattheisen [verfasserIn] Francis McMahon [verfasserIn] Bruno Müller-Oerlinghausen [verfasserIn] Markus M. Nöthen [verfasserIn] Marco Pinna [verfasserIn] Claudia Pisanu [verfasserIn] Claire O’Donovan [verfasserIn] Marcella D. C. Rietschel [verfasserIn] Guy Rouleau [verfasserIn] Thomas Schulze [verfasserIn] Giovanni Severino [verfasserIn] Claire M. Slaney [verfasserIn] Alessio Squassina [verfasserIn] Aleksandra Suwalska [verfasserIn] Gustavo Turecki [verfasserIn] Rudolf Uher [verfasserIn] Petr Zvolsky [verfasserIn] Pablo Cervantes [verfasserIn] Maria del Zompo [verfasserIn] Paul Grof [verfasserIn] Janusz Rybakowski [verfasserIn] Leonardo Tondo [verfasserIn] Thomas Trappenberg [verfasserIn] Martin Alda [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021 |
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| Übergeordnetes Werk: |
In: Translational Psychiatry - Nature Publishing Group, 2012, 11(2021), 1, Seite 13 |
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| Übergeordnetes Werk: |
volume:11 ; year:2021 ; number:1 ; pages:13 |
| Links: |
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| DOI / URN: |
10.1038/s41398-020-01148-y |
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DOAJ050412884 |
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| 520 | |a 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. | ||
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10.1038/s41398-020-01148-y doi (DE-627)DOAJ050412884 (DE-599)DOAJ148507cd1abd48b0b4092cfa43da61f1 DE-627 ger DE-627 rakwb eng RC321-571 Abraham Nunes verfasserin aut Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurosciences. Biological psychiatry. Neuropsychiatry William Stone verfasserin aut Raffaella Ardau verfasserin aut Anne Berghöfer verfasserin aut Alberto Bocchetta verfasserin aut Caterina Chillotti verfasserin aut Valeria Deiana verfasserin aut Franziska Degenhardt verfasserin aut Andreas J. Forstner verfasserin aut Julie S. Garnham verfasserin aut Eva Grof verfasserin aut Tomas Hajek verfasserin aut Mirko Manchia verfasserin aut Manuel Mattheisen verfasserin aut Francis McMahon verfasserin aut Bruno Müller-Oerlinghausen verfasserin aut Markus M. Nöthen verfasserin aut Marco Pinna verfasserin aut Claudia Pisanu verfasserin aut Claire O’Donovan verfasserin aut Marcella D. C. Rietschel verfasserin aut Guy Rouleau verfasserin aut Thomas Schulze verfasserin aut Giovanni Severino verfasserin aut Claire M. Slaney verfasserin aut Alessio Squassina verfasserin aut Aleksandra Suwalska verfasserin aut Gustavo Turecki verfasserin aut Rudolf Uher verfasserin aut Petr Zvolsky verfasserin aut Pablo Cervantes verfasserin aut Maria del Zompo verfasserin aut Paul Grof verfasserin aut Janusz Rybakowski verfasserin aut Leonardo Tondo verfasserin aut Thomas Trappenberg verfasserin aut Martin Alda verfasserin aut In Translational Psychiatry Nature Publishing Group, 2012 11(2021), 1, Seite 13 (DE-627)660807378 (DE-600)2609311-X 21583188 nnns volume:11 year:2021 number:1 pages:13 https://doi.org/10.1038/s41398-020-01148-y kostenfrei https://doaj.org/article/148507cd1abd48b0b4092cfa43da61f1 kostenfrei https://doi.org/10.1038/s41398-020-01148-y kostenfrei https://doaj.org/toc/2158-3188 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 13 |
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10.1038/s41398-020-01148-y doi (DE-627)DOAJ050412884 (DE-599)DOAJ148507cd1abd48b0b4092cfa43da61f1 DE-627 ger DE-627 rakwb eng RC321-571 Abraham Nunes verfasserin aut Exemplar scoring identifies genetically separable phenotypes of lithium responsive bipolar disorder 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Neurosciences. Biological psychiatry. Neuropsychiatry William Stone verfasserin aut Raffaella Ardau verfasserin aut Anne Berghöfer verfasserin aut Alberto Bocchetta verfasserin aut Caterina Chillotti verfasserin aut Valeria Deiana verfasserin aut Franziska Degenhardt verfasserin aut Andreas J. Forstner verfasserin aut Julie S. Garnham verfasserin aut Eva Grof verfasserin aut Tomas Hajek verfasserin aut Mirko Manchia verfasserin aut Manuel Mattheisen verfasserin aut Francis McMahon verfasserin aut Bruno Müller-Oerlinghausen verfasserin aut Markus M. Nöthen verfasserin aut Marco Pinna verfasserin aut Claudia Pisanu verfasserin aut Claire O’Donovan verfasserin aut Marcella D. C. Rietschel verfasserin aut Guy Rouleau verfasserin aut Thomas Schulze verfasserin aut Giovanni Severino verfasserin aut Claire M. Slaney verfasserin aut Alessio Squassina verfasserin aut Aleksandra Suwalska verfasserin aut Gustavo Turecki verfasserin aut Rudolf Uher verfasserin aut Petr Zvolsky verfasserin aut Pablo Cervantes verfasserin aut Maria del Zompo verfasserin aut Paul Grof verfasserin aut Janusz Rybakowski verfasserin aut Leonardo Tondo verfasserin aut Thomas Trappenberg verfasserin aut Martin Alda verfasserin aut In Translational Psychiatry Nature Publishing Group, 2012 11(2021), 1, Seite 13 (DE-627)660807378 (DE-600)2609311-X 21583188 nnns volume:11 year:2021 number:1 pages:13 https://doi.org/10.1038/s41398-020-01148-y kostenfrei https://doaj.org/article/148507cd1abd48b0b4092cfa43da61f1 kostenfrei https://doi.org/10.1038/s41398-020-01148-y kostenfrei https://doaj.org/toc/2158-3188 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2021 1 13 |
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Abraham Nunes @@aut@@ William Stone @@aut@@ Raffaella Ardau @@aut@@ Anne Berghöfer @@aut@@ Alberto Bocchetta @@aut@@ Caterina Chillotti @@aut@@ Valeria Deiana @@aut@@ Franziska Degenhardt @@aut@@ Andreas J. Forstner @@aut@@ Julie S. Garnham @@aut@@ Eva Grof @@aut@@ Tomas Hajek @@aut@@ Mirko Manchia @@aut@@ Manuel Mattheisen @@aut@@ Francis McMahon @@aut@@ Bruno Müller-Oerlinghausen @@aut@@ Markus M. Nöthen @@aut@@ Marco Pinna @@aut@@ Claudia Pisanu @@aut@@ Claire O’Donovan @@aut@@ Marcella D. C. Rietschel @@aut@@ Guy Rouleau @@aut@@ Thomas Schulze @@aut@@ Giovanni Severino @@aut@@ Claire M. Slaney @@aut@@ Alessio Squassina @@aut@@ Aleksandra Suwalska @@aut@@ Gustavo Turecki @@aut@@ Rudolf Uher @@aut@@ Petr Zvolsky @@aut@@ Pablo Cervantes @@aut@@ Maria del Zompo @@aut@@ Paul Grof @@aut@@ Janusz Rybakowski @@aut@@ Leonardo Tondo @@aut@@ Thomas Trappenberg @@aut@@ Martin Alda @@aut@@ |
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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. |
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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. |
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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. |
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