Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

International Consortium on Lithium Genetics (ConLi+Gen)

doi:10.1001/jamapsychiatry.2017.3433

Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

International Consortium on Lithium Genetics (ConLi+Gen)

Medicine

Résultat de recherche: Article › examen par les pairs

155 Citations (Scopus)

Résumé

IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

Langue d'origine	English
Pages (de-à)	65-74
Nombre de pages	10
Journal	JAMA Psychiatry
Volume	75
Numéro de publication	1
DOI	https://doi.org/10.1001/jamapsychiatry.2017.3433
Statut de publication	Published - janv. 2018

Note bibliographique

Funding Information:
Postgraduate Research Scholarship support from the University of Adelaide through the Adelaide Scholarship International (ASI) program. The primary sources of funding were grants RI 908/7-1, FOR2107 and RI 908/11-1 from the Deutsche Forschungsgemeinschaft (Dr Rietschel) and grant NO 246/10-1 (Dr Nöthen) and grant ZIA-MH00284311 from the Intramural Research Program of the National Institute of Mental Health (ClinicalTrials.gov identifier: NCT00001174). The genotyping was funded in part by the German Federal Ministry of Education and Research through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (Drs Schulze, Rietschel, and Nöthen). This study was supported by National Institutes of Health grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by grant 64410 from the Canadian Institutes of Health Research (Dr Alda). Collection and phenotyping of the Australian University of New South Wales sample was funded by program grant 1037196 from the Australian National Health and Medical Research Council (Mr Mitchell, Dr Schofield, Dr Fullerton, and Mr Wright). The collection of the Barcelona sample was supported by grants PI080247, PI1200906, PI12/00018, 2014SGR1636, 2014SGR398, and MSII14/00030 from the Centro de Investigación en Red de Salud Mental, Institut d’Investigacions Biomèdiques August Pi i Sunyer, the Centres de Recerca de Catalunya Programme/Generalitat de Catalunya, and the Miguel Servet II and Instituto de Salud Carlos III. The Swedish Research Council, the Stockholm County Council, Karolinska Institutet, and the Söderström-Königska Foundation supported this research through grants awarded to Drs Backlund, Frisen, Lavebratt, and Schalling. The collection of the Geneva sample was supported by grants Synapsy–The Synaptic Basis of Mental Diseases 51NF40-158776 and 32003B-125469 from the Swiss National Foundation. The work by the French group was supported by INSERM (Institut National de la Santé et de la Recherche Médicale), AP-HP (Assistance Publique des Hôpitaux de Paris), the Fondation FondaMental (RTRS Santé Mentale), and the labex Bio-PSY (Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02). The collection of the Romanian sample was supported by a grant from Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (Dr Grigoroiu-Serbanescu).The collection of the Czech sample was supported by the project Nr. LO1611 with a financial support from the MEYS under the NPU I program and by the Czech Science Foundation, grant Nr. 17-07070S.

ASJC Scopus Subject Areas

Psychiatry and Mental health

PubMed: MeSH publication types

Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1001/jamapsychiatry.2017.3433

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@article{0994a1e07f684edcb246c14132b21e25,

title = "Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study",

abstract = "IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.",

author = "{International Consortium on Lithium Genetics (ConLi+Gen)} and Amare, {Azmeraw T.} and Schubert, {Klaus Oliver} and Liping Hou and Clark, {Scott R.} and Sergi Papiol and Urs Heilbronner and Franziska Degenhardt and Fasil Tekola-Ayele and Hsu, {Yi Hsiang} and Tatyana Shekhtman and Mazda Adli and Nirmala Akula and Kazufumi Akiyama and Raffaella Ardau and B{\'a}rbara Arias and Aubry, {Jean Michel} and Lena Backlund and Bhattacharjee, {Abesh Kumar} and Frank Bellivier and Antonio Benabarre and Susanne Bengesser and Biernacka, {Joanna M.} and Armin Birner and Clara Brichant-Petitjean and Pablo Cervantes and Chen, {Hsi Chung} and Caterina Chillotti and Sven Cichon and Cristiana Cruceanu and Czerski, {Piotr M.} and Nina Dalkner and Alexandre Dayer and {Del Zompo}, Maria and DePaulo, {J. Raymond} and Bruno {\'E}tain and Peter Falkai and Forstner, {Andreas J.} and Louise Frisen and Frye, {Mark A.} and Fullerton, {Janice M.} and S{\'e}bastien Gard and Garnham, {Julie S.} and Goes, {Fernando S.} and Maria Grigoroiu-Serbanescu and Paul Grof and Ryota Hashimoto and Joanna Hauser and Mirko Manchia and Claire O'Donovan and Slaney, {Claire M.}",

note = "Funding Information: Postgraduate Research Scholarship support from the University of Adelaide through the Adelaide Scholarship International (ASI) program. The primary sources of funding were grants RI 908/7-1, FOR2107 and RI 908/11-1 from the Deutsche Forschungsgemeinschaft (Dr Rietschel) and grant NO 246/10-1 (Dr N{\"o}then) and grant ZIA-MH00284311 from the Intramural Research Program of the National Institute of Mental Health (ClinicalTrials.gov identifier: NCT00001174). The genotyping was funded in part by the German Federal Ministry of Education and Research through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (Drs Schulze, Rietschel, and N{\"o}then). This study was supported by National Institutes of Health grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by grant 64410 from the Canadian Institutes of Health Research (Dr Alda). Collection and phenotyping of the Australian University of New South Wales sample was funded by program grant 1037196 from the Australian National Health and Medical Research Council (Mr Mitchell, Dr Schofield, Dr Fullerton, and Mr Wright). The collection of the Barcelona sample was supported by grants PI080247, PI1200906, PI12/00018, 2014SGR1636, 2014SGR398, and MSII14/00030 from the Centro de Investigaci{\'o}n en Red de Salud Mental, Institut d{\textquoteright}Investigacions Biom{\`e}diques August Pi i Sunyer, the Centres de Recerca de Catalunya Programme/Generalitat de Catalunya, and the Miguel Servet II and Instituto de Salud Carlos III. The Swedish Research Council, the Stockholm County Council, Karolinska Institutet, and the S{\"o}derstr{\"o}m-K{\"o}nigska Foundation supported this research through grants awarded to Drs Backlund, Frisen, Lavebratt, and Schalling. The collection of the Geneva sample was supported by grants Synapsy–The Synaptic Basis of Mental Diseases 51NF40-158776 and 32003B-125469 from the Swiss National Foundation. The work by the French group was supported by INSERM (Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale), AP-HP (Assistance Publique des H{\^o}pitaux de Paris), the Fondation FondaMental (RTRS Sant{\'e} Mentale), and the labex Bio-PSY (Investissements d{\textquoteright}Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02). The collection of the Romanian sample was supported by a grant from Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (Dr Grigoroiu-Serbanescu).The collection of the Czech sample was supported by the project Nr. LO1611 with a financial support from the MEYS under the NPU I program and by the Czech Science Foundation, grant Nr. 17-07070S.",

year = "2018",

month = jan,

doi = "10.1001/jamapsychiatry.2017.3433",

language = "English",

volume = "75",

pages = "65--74",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "American Medical Association",

number = "1",

}

TY - JOUR

T1 - Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder

T2 - A genome-wide association study

AU - International Consortium on Lithium Genetics (ConLi+Gen)

AU - Amare, Azmeraw T.

AU - Schubert, Klaus Oliver

AU - Hou, Liping

AU - Clark, Scott R.

AU - Papiol, Sergi

AU - Heilbronner, Urs

AU - Degenhardt, Franziska

AU - Tekola-Ayele, Fasil

AU - Hsu, Yi Hsiang

AU - Shekhtman, Tatyana

AU - Adli, Mazda

AU - Akula, Nirmala

AU - Akiyama, Kazufumi

AU - Ardau, Raffaella

AU - Arias, Bárbara

AU - Aubry, Jean Michel

AU - Backlund, Lena

AU - Bhattacharjee, Abesh Kumar

AU - Bellivier, Frank

AU - Benabarre, Antonio

AU - Bengesser, Susanne

AU - Biernacka, Joanna M.

AU - Birner, Armin

AU - Brichant-Petitjean, Clara

AU - Cervantes, Pablo

AU - Chen, Hsi Chung

AU - Chillotti, Caterina

AU - Cichon, Sven

AU - Cruceanu, Cristiana

AU - Czerski, Piotr M.

AU - Dalkner, Nina

AU - Dayer, Alexandre

AU - Del Zompo, Maria

AU - DePaulo, J. Raymond

AU - Étain, Bruno

AU - Falkai, Peter

AU - Forstner, Andreas J.

AU - Frisen, Louise

AU - Frye, Mark A.

AU - Fullerton, Janice M.

AU - Gard, Sébastien

AU - Garnham, Julie S.

AU - Goes, Fernando S.

AU - Grigoroiu-Serbanescu, Maria

AU - Grof, Paul

AU - Hashimoto, Ryota

AU - Hauser, Joanna

AU - Manchia, Mirko

AU - O'Donovan, Claire

AU - Slaney, Claire M.

N1 - Funding Information: Postgraduate Research Scholarship support from the University of Adelaide through the Adelaide Scholarship International (ASI) program. The primary sources of funding were grants RI 908/7-1, FOR2107 and RI 908/11-1 from the Deutsche Forschungsgemeinschaft (Dr Rietschel) and grant NO 246/10-1 (Dr Nöthen) and grant ZIA-MH00284311 from the Intramural Research Program of the National Institute of Mental Health (ClinicalTrials.gov identifier: NCT00001174). The genotyping was funded in part by the German Federal Ministry of Education and Research through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (Drs Schulze, Rietschel, and Nöthen). This study was supported by National Institutes of Health grants P50CA89392 from the National Cancer Institute and 5K02DA021237 from the National Institute of Drug Abuse. The Canadian part of the study was supported by grant 64410 from the Canadian Institutes of Health Research (Dr Alda). Collection and phenotyping of the Australian University of New South Wales sample was funded by program grant 1037196 from the Australian National Health and Medical Research Council (Mr Mitchell, Dr Schofield, Dr Fullerton, and Mr Wright). The collection of the Barcelona sample was supported by grants PI080247, PI1200906, PI12/00018, 2014SGR1636, 2014SGR398, and MSII14/00030 from the Centro de Investigación en Red de Salud Mental, Institut d’Investigacions Biomèdiques August Pi i Sunyer, the Centres de Recerca de Catalunya Programme/Generalitat de Catalunya, and the Miguel Servet II and Instituto de Salud Carlos III. The Swedish Research Council, the Stockholm County Council, Karolinska Institutet, and the Söderström-Königska Foundation supported this research through grants awarded to Drs Backlund, Frisen, Lavebratt, and Schalling. The collection of the Geneva sample was supported by grants Synapsy–The Synaptic Basis of Mental Diseases 51NF40-158776 and 32003B-125469 from the Swiss National Foundation. The work by the French group was supported by INSERM (Institut National de la Santé et de la Recherche Médicale), AP-HP (Assistance Publique des Hôpitaux de Paris), the Fondation FondaMental (RTRS Santé Mentale), and the labex Bio-PSY (Investissements d’Avenir program managed by the ANR under reference ANR-11-IDEX-0004-02). The collection of the Romanian sample was supported by a grant from Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (Dr Grigoroiu-Serbanescu).The collection of the Czech sample was supported by the project Nr. LO1611 with a financial support from the MEYS under the NPU I program and by the Czech Science Foundation, grant Nr. 17-07070S.

PY - 2018/1

Y1 - 2018/1

N2 - IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

AB - IMPORTANCE Lithium is a first-line mood stabilizer for the treatment of bipolar affective disorder (BPAD). However, the efficacy of lithium varies widely, with a nonresponse rate of up to 30%. Biological response markers are lacking. Genetic factors are thought to mediate treatment response to lithium, and there is a previously reported genetic overlap between BPAD and schizophrenia (SCZ). OBJECTIVES To test whether a polygenic score for SCZ is associated with treatment response to lithium in BPAD and to explore the potential molecular underpinnings of this association. DESIGN, SETTING, AND PARTICIPANTS A total of 2586 patients with BPAD who had undergone lithium treatment were genotyped and assessed for long-term response to treatment between 2008 and 2013.Weighted SCZ polygenic scores were computed at different P value thresholds using summary statistics from an international multicenter genome-wide association study (GWAS) of 36 989 individuals with SCZ and genotype data from patients with BPAD from the Consortium on Lithium Genetics. For functional exploration, a cross-trait meta-GWAS and pathway analysis was performed, combining GWAS summary statistics on SCZ and response to treatment with lithium. Data analysis was performed from September 2016 to February 2017. MAIN OUTCOMES AND MEASURES Treatment response to lithiumwas defined on both the categorical and continuous scales using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. The effect measures include odds ratios and the proportion of variance explained. RESULTS Of the 2586 patients in the study (mean [SD] age, 47.2 [13.9] years), 1478 were women and 1108 were men. The polygenic score for SCZ was inversely associated with lithium treatment response in the categorical outcome, at a threshold P < 5 ? 10-2. Patients with BPAD who had a low polygenic load for SCZ responded better to lithium, with odds ratios for lithium response ranging from 3.46 (95%CI, 1.42-8.41) at the first decile to 2.03 (95%CI, 0.86-4.81) at the ninth decile, compared with the patients in the 10th decile of SCZ risk. In the cross-trait meta-GWAS, 15 genetic loci that may have overlapping effects on lithium treatment response and susceptibility to SCZ were identified. Functional pathway and network analysis of these loci point to the HLA antigen complex and inflammatory cytokines. CONCLUSIONS AND RELEVANCE This study provides evidence for a negative association between high genetic loading for SCZ and poor response to lithium in patients with BPAD. These results suggest the potential for translational research aimed at personalized prescribing of lithium.

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UR - http://www.scopus.com/inward/citedby.url?scp=85040465816&partnerID=8YFLogxK

U2 - 10.1001/jamapsychiatry.2017.3433

DO - 10.1001/jamapsychiatry.2017.3433

M3 - Article

C2 - 29121268

AN - SCOPUS:85040465816

SN - 2168-622X

VL - 75

SP - 65

EP - 74

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 1

ER -

Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study

Résumé

Note bibliographique

ASJC Scopus Subject Areas

PubMed: MeSH publication types

ODD de l’ONU

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