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)

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)65-74
Number of pages10
JournalJAMA Psychiatry
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2018

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Genome-Wide Association Study
HLA Antigens
Mood Disorders
Bipolar Disorder
Lithium
Schizophrenia
Inflammation
Genes
Therapeutics
Odds Ratio
Research Subjects
Genetic Loci
Translational Medical Research
Biomarkers
Genotype

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

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).

In: JAMA Psychiatry, Vol. 75, No. 1, 01.01.2018, p. 65-74.

Research output: Contribution to journalArticle

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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 Stefan Herms and Per Hoffmann and Andrea Hofmann",
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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 - Herms, Stefan

AU - Hoffmann, Per

AU - Hofmann, Andrea

PY - 2018/1/1

Y1 - 2018/1/1

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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