Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Azmeraw T Amare; Bernhard T Baune; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium; A. Abdellaoui; C.V. Dolan; Jouke Jan  Hottenga; Hamdi Mbarek; C.M. Middeldorp; Michel G. Nivard; Gonneke Willemsen; D.I. Boomsma; Eco J.C. de Geus; Aartjan F T Beekman; Rick Jansen; Yuri Milaneschi; Wouter J Peyrot; Johannes H. Smit; Brenda W J H Penninx; Danielle Posthuma

doi:10.1038/s41380-020-0689-5

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

Azmeraw T Amare, Bernhard T Baune, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, A. Abdellaoui, C.V. Dolan, Jouke Jan Hottenga, Hamdi Mbarek, C.M. Middeldorp, Michel G. Nivard, Gonneke Willemsen, D.I. Boomsma, Eco J.C. de Geus, Aartjan F T Beekman, Rick Jansen, Yuri Milaneschi, Wouter J Peyrot, Johannes H. Smit, Brenda W J H Penninx, Danielle Posthuma

Research output: Contribution to Journal › Article › Academic › peer-review

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Abstract

Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

Original language	English
Pages (from-to)	2457-2470
Number of pages	14
Journal	Molecular Psychiatry
Volume	26
Issue number	6
Early online date	16 Mar 2020
DOIs	https://doi.org/10.1038/s41380-020-0689-5
Publication status	Published - Jun 2021

Funding

Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, USA; 213Faculty of Medicine, University of Iceland, Reykjavik, Iceland; 214Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, the Netherlands; 215Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, the Netherlands; 216Psychiatry, Dalhousie University, Halifax, NS, Canada; 217Division of Epidemiology, New York State Psychiatric Institute, New York, NY, USA; 218Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; 219Department of Medical & Molecular Genetics, King’s College London, London, GB, UK; 220Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, USA; 221NIHR BRC for Mental Health, King’s College London, London, GB, UK; 222Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 223Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Funding ATA received a Postgraduate Research Scholarship support from the University of Adelaide through the Adelaide Scholarship International (ASI) program. We thank 23andMe, Inc. staffs for giving us the permission to utilize GWAS summary data for depression which was included as part of the Psychiatric Genomics Consortium (PGC) study. The primary sources of funding were the Deutsche For-schungsgemeinschaft (DFG; grant no. RI 908/7–1; grant FOR2107, RI 908/11–1 to MR, NO 246/10–1 to MMN, WI3429/3–1 to SHW) and the Intramural Research Program of the National Institute of Mental Health (ZIA-MH00284311; ClinicalTrials.gov identifier: NCT00001174). The genotyping was in part funded by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network Inte-graMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), under the auspices of the e:Med Programme (grants awarded to TGS, MR, and MMN). Some data and biomaterials were collected as part of eleven projects (Study 40) that participated in the National Institute of Mental Health (NIMH) Bipolar Disorder Genetics Initiative. From 2003–2007, the Principal Investigators and CoInvestigators were: Indiana University, Indianapolis, IN, R01 MH59545, John Nurnberger, M.D., Ph.D., Marvin J. Miller, M.D., Elizabeth S. Bowman, M.D., N. Leela Rau, M.D., P. Ryan Moe, M.D., Nalini Samavedy, M.D., Rif El-Mallakh, M.D. (at University of Louisville), Husseini Manji, M.D. (at Johnson and Johnson), Debra A.Glitz, M.D. (at Wayne State University), Eric T. Meyer, Ph.D., M.S. (at Oxford University, UK), Carrie Smiley, R.N., Tatiana Foroud, Ph.D., Leah Flury, M.S., Danielle M. Dick, Ph.D. (at Virginia Commonwealth University), Howard Edenberg, Ph.D.; Washington University, St. Louis, MO, R01 MH059534, John Rice, Ph.D., Theodore Reich, M.D., Allison Goate, Ph.D., Laura Bierut, M.D.K02 DA21237; Johns Hopkins University, Baltimore, M.D., R01 MH59533, Melvin McInnis, M.D., JRD, M.D., Dean F. MacKinnon, M.D., FMM, M.D., JBP, M.D., PPZ, Ph.D., Dimitrios Avramopoulos, and Jennifer Payne; University of Pennsylvania, PA, R01 MH59553, Wade Berrettini, M.D., Ph.D.; University of California at San Francisco, CA, R01 MH60068, William Byerley, M. D., and Sophia Vinogradov, M.D.; University of Iowa, IA, R01 MH059548, William Coryell, M.D., and Raymond Crowe, M.D.; University of Chicago, IL, R01 MH59535, Elliot Gershon, M.D., Judith Badner, Ph.D., Francis McMahon, M.D., Chunyu Liu, Ph.D., Alan Sanders, M.D., Maria Caserta, Steven Dinwiddie, M.D., Tu Nguyen, Donna Harakal; University of California at San Diego, CA, R01 MH59567, JK, M.D., Rebecca McKinney, B.A.; Rush University, IL, R01 MH059556, William Scheftner, M.D., Howard M. Kravitz, D.O., M.P.H., Diana Marta, B.S., Annette Vaughn-Brown, M.S.N., R.N., and Laurie Bederow, M.A.; NIMH Intramural Research Program, Bethesda, MD, 1Z01MH002810-01, FJM, M.D., LK, Psy.D., Sevilla Detera-Wadleigh, Ph.D., Lisa Austin, Ph.D., Dennis L. Murphy, M.D.; Howard University, William B. Lawson, M.D., Ph.D., Evarista Nwulia, M.D., and Maria Hipolito, M.D. This work was supported by the NIH 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 the Canadian Institutes of Health Research to MA grant #64410 to MA. Collection and phenotyping of the Australian UNSW sample, by PBM, PRS, JMF and AW, was funded by an Australian NHMRC Program Grant (No.1037196)), with personnel supported by NHMRC project grants (Nos. 1063960, 1066177) and the Janette Mary O’Neil Research Fellowship to JMF. The collection of the Barcelona sample was supported by the Centro de Investigación en Red de Salud Mental (CIBERSAM), IDIBAPS, the CERCA Programme / Generalitat de Catalunya, Miguel Servet II and Instituto de Salud Carlos III (grant numbers PI080247, PI1200906, PI12/00018, 2017 SGR 1577 and 2017 SGR 1365). Dr FC was funded by unrestricted funding from CIBERSAM and “Secretaria d′Universitats i Recerca del Departament d′ Economia i Coneixement (2017 SGR 134), Generalitat de Catalunya (Government of Catalonia). The Swedish Research Council, the Stockholm County Council, Karolinska Institutet and the Söderström-Königska Foundation supported this research through grants awarded to LB, LF, CL and MS. The collection of the Geneva sample was supported by the Swiss National Foundation (grants Synapsy 51NF40-158776 and 32003B-125469). 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 German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5–2 to UD; SFB-TRR58, Project C09 and Z02 to UD), and the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of the University of Münster (grant Dan3/012/17 to UD) supported this work. The collection of the Romanian sample was supported by U.E.F.I.S.C.D.I., Romania, grant awarded to MG-S. The collection of the Czech sample was supported by the project No. LO1611 with a financial support from the MEYS under the NPU I program and by the Czech Science Foundation, grant No. 17-07070S.

Funders	Funder number
213Faculty of Medicine, University of Iceland	215Psychiatry
217Division of Epidemiology, New York State Psychiatric Institute
218Department of Clinical Medicine, University of Copenhagen
220Psychiatry & Behavioral Sciences
221NIHR BRC for Mental Health	222Genetics
ANR-11-IDEX-0004-02
Erasmus MC, Rotterdam
Integrated Network Inte-graMent
NIMH Division of Intramural Research Programs
Söderström-Königska Foundation
U.E.F.I.S.C.D.I.	LO1611
Zuid-Holland
National Institutes of Health	P50CA89392
National Institute of Mental Health	ZIA-MH00284311, NCT00001174
National Institute on Drug Abuse
National Cancer Institute	5K02DA021237
U.S. Department of Veterans Affairs	I01BX003431
Stanford University
University of North Carolina at Chapel Hill
King’s College London
Fondation FondaMental
Canadian Institutes of Health Research	64410
National Health and Medical Research Council	1037196, 1063960, 1066177
Deutsche Forschungsgemeinschaft	FOR2107, DA1151/5–2, RI 908/7–1, SFB-TRR58, WI3429/3–1, RI 908/11–1, FOR2107 DA1151/5-1, 246/10–1
Agence Nationale de la Recherche
Institut national de la santé et de la recherche médicale
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	32003B-125469, 51NF40-158776
University of Adelaide
Ministerstvo Školství, Mládeže a Tělovýchovy
Grantová Agentura České Republiky	17-07070S
Bundesministerium für Bildung und Forschung
Generalitat de Catalunya
Dalhousie University
Karolinska Institutet
Stockholms Läns Landsting
Vetenskapsrådet
Instituto de Salud Carlos III	PI1200906, PI12/00018, 2017 SGR 1577, 2017 SGR 134, 2017 SGR 1365, PI080247
Westfälische Wilhelms-Universität Münster	Dan3/012/17
Centro de Investigación Biomédica en Red de Salud Mental
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
Institut d’Investigacions Biomèdiques August Pi i Sunyer, Universitat de Barcelona

Cohort Studies

Netherlands Twin Register (NTR)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41380-020-0689-5

Association of polygenic score for major depression with response to lithium in patients with bipolar disorderFinal published version, 2.18 MBLicence: Article 25fa Dutch Copyright Act

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Amare, A. T., Baune, B. T., Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Abdellaoui, A., Dolan, C. V., Hottenga, J. J., Mbarek, H., Middeldorp, C. M., Nivard, M. G., Willemsen, G., Boomsma, D. I., de Geus, E. J. C., Beekman, A. F. T., Jansen, R., Milaneschi, Y., Peyrot, W. J., Smit, J. H., W J H Penninx, B., & Posthuma, D. (2021). Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry, 26(6), 2457-2470. https://doi.org/10.1038/s41380-020-0689-5

@article{665fd2bacb01470c92003b5fdaf53d80,

title = "Association of polygenic score for major depression with response to lithium in patients with bipolar disorder",

abstract = "Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.",

author = "Amare, {Azmeraw T} and Schubert, {Klaus Oliver} and Liping Hou and Clark, {Scott R} and Sergi Papiol and Micah Cearns and Urs Heilbronner and Franziska Degenhardt and Fasil Tekola-Ayele and Yi-Hsiang Hsu and Tatyana Shekhtman and Mazda Adli and Nirmala Akula and Kazufumi Akiyama and Raffaella Ardau and B{\'a}rbara Arias and Jean-Michel Aubry 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 Hsi-Chung Chen 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 Stephane Jamain 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 and Esther Jim{\'e}nez and Jean-Pierre Kahn and Layla Kassem and Po-Hsiu Kuo and Tadafumi Kato and Kelsoe, {John R} and Sarah Kittel-Schneider and Sebastian Kliwicki and Barbara K{\"o}nig and Ichiro Kusumi and Gonzalo Laje and Mikael Land{\'e}n and Catharina Lavebratt and Marion Leboyer and Leckband, {Susan G} and Alfonso Tortorella and Mirko Manchia and Lina Martinsson and McCarthy, {Michael J} and McElroy, {Susan L} and Francesc Colom and Marina Mitjans and Mondimore, {Francis M} and Palmiero Monteleone and Nievergelt, {Caroline M} and N{\"o}then, {Markus M} and Tomas Nov{\'a}k and Claire O'Donovan and Norio Ozaki and Urban {\"O}sby and Andrea Pfennig and Potash, {James B} and Andreas Reif and Eva Reininghaus and Rouleau, {Guy A} and Rybakowski, {Janusz K} and Martin Schalling and Schofield, {Peter R} and Schweizer, {Barbara W} and Giovanni Severino and Shilling, {Paul D} and Katzutaka Shimoda and Christian Simhandl and Slaney, {Claire M} and Alessio Squassina and Thomas Stamm and Pavla Stopkova and Mario Maj and Gustavo Turecki and Eduard Vieta and Julia Veeh and Witt, {Stephanie H} and Adam Wright and Zandi, {Peter P} and Mitchell, {Philip B} and Michael Bauer and Martin Alda and Marcella Rietschel and McMahon, {Francis J} and Schulze, {Thomas G} and Baune, {Bernhard T} and {Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium} and A. Abdellaoui and C.V. Dolan and Hottenga, {Jouke Jan} and Hamdi Mbarek and C.M. Middeldorp and Nivard, {Michel G.} and Gonneke Willemsen and D.I. Boomsma and {de Geus}, {Eco J.C.} and Beekman, {Aartjan F T} and Rick Jansen and Yuri Milaneschi and Peyrot, {Wouter J} and Smit, {Johannes H.} and {W J H Penninx}, Brenda and Danielle Posthuma",

year = "2021",

month = jun,

doi = "10.1038/s41380-020-0689-5",

language = "English",

volume = "26",

pages = "2457--2470",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "6",

}

Amare, AT, Baune, BT, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Abdellaoui, A, Dolan, CV , Hottenga, JJ, Mbarek, H, Middeldorp, CM, Nivard, MG , Willemsen, G , Boomsma, DI , de Geus, EJC, Beekman, AFT, Jansen, R, Milaneschi, Y, Peyrot, WJ, Smit, JH, W J H Penninx, B & Posthuma, D 2021, 'Association of polygenic score for major depression with response to lithium in patients with bipolar disorder', Molecular Psychiatry, vol. 26, no. 6, pp. 2457-2470. https://doi.org/10.1038/s41380-020-0689-5

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. / Amare, Azmeraw T; Baune, Bernhard T; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium et al.
In: Molecular Psychiatry, Vol. 26, No. 6, 06.2021, p. 2457-2470.

Research output: Contribution to Journal › Article › Academic › peer-review

TY - JOUR

T1 - Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

AU - Amare, Azmeraw T

AU - Schubert, Klaus Oliver

AU - Hou, Liping

AU - Clark, Scott R

AU - Papiol, Sergi

AU - Cearns, Micah

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 - Jamain, Stephane

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

AU - Jiménez, Esther

AU - Kahn, Jean-Pierre

AU - Kassem, Layla

AU - Kuo, Po-Hsiu

AU - Kato, Tadafumi

AU - Kelsoe, John R

AU - Kittel-Schneider, Sarah

AU - Kliwicki, Sebastian

AU - König, Barbara

AU - Kusumi, Ichiro

AU - Laje, Gonzalo

AU - Landén, Mikael

AU - Lavebratt, Catharina

AU - Leboyer, Marion

AU - Leckband, Susan G

AU - Tortorella, Alfonso

AU - Manchia, Mirko

AU - Martinsson, Lina

AU - McCarthy, Michael J

AU - McElroy, Susan L

AU - Colom, Francesc

AU - Mitjans, Marina

AU - Mondimore, Francis M

AU - Monteleone, Palmiero

AU - Nievergelt, Caroline M

AU - Nöthen, Markus M

AU - Novák, Tomas

AU - O'Donovan, Claire

AU - Ozaki, Norio

AU - Ösby, Urban

AU - Pfennig, Andrea

AU - Potash, James B

AU - Reif, Andreas

AU - Reininghaus, Eva

AU - Rouleau, Guy A

AU - Rybakowski, Janusz K

AU - Schalling, Martin

AU - Schofield, Peter R

AU - Schweizer, Barbara W

AU - Severino, Giovanni

AU - Shilling, Paul D

AU - Shimoda, Katzutaka

AU - Simhandl, Christian

AU - Slaney, Claire M

AU - Squassina, Alessio

AU - Stamm, Thomas

AU - Stopkova, Pavla

AU - Maj, Mario

AU - Turecki, Gustavo

AU - Vieta, Eduard

AU - Veeh, Julia

AU - Witt, Stephanie H

AU - Wright, Adam

AU - Zandi, Peter P

AU - Mitchell, Philip B

AU - Bauer, Michael

AU - Alda, Martin

AU - Rietschel, Marcella

AU - McMahon, Francis J

AU - Schulze, Thomas G

AU - Baune, Bernhard T

AU - Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium

AU - Abdellaoui, A.

AU - Dolan, C.V.

AU - Hottenga, Jouke Jan

AU - Mbarek, Hamdi

AU - Middeldorp, C.M.

AU - Nivard, Michel G.

AU - Willemsen, Gonneke

AU - Boomsma, D.I.

AU - de Geus, Eco J.C.

AU - Beekman, Aartjan F T

AU - Jansen, Rick

AU - Milaneschi, Yuri

AU - Peyrot, Wouter J

AU - Smit, Johannes H.

AU - W J H Penninx, Brenda

AU - Posthuma, Danielle

PY - 2021/6

Y1 - 2021/6

N2 - Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

AB - Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18-2.01) and European sample: OR = 1.75 (95% CI: 1.30-2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61-4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

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UR - http://www.scopus.com/inward/citedby.url?scp=85081737215&partnerID=8YFLogxK

U2 - 10.1038/s41380-020-0689-5

DO - 10.1038/s41380-020-0689-5

M3 - Article

C2 - 32203155

SN - 1359-4184

VL - 26

SP - 2457

EP - 2470

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 6

ER -

Association of polygenic score for major depression with response to lithium in patients with bipolar disorder

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