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 |
| DOIs | |
| Publication status | Published - Jun 2021 |
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. / Amare, Azmeraw T.; Schubert, Klaus Oliver; Hou, Liping 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 - Wray, Naomi R.
AU - Ripke, Stephan
AU - Mattheisen, Manuel
AU - Trzaskowski, Maciej
AU - Byrne, Enda M.
AU - Abdellaoui, Abdel
AU - Adams, Mark J.
AU - Agerbo, Esben
AU - Air, Tracy M.
AU - Andlauer, Till F.M.
AU - Bacanu, Silviu Alin
AU - Bækvad-Hansen, Marie
AU - Beekman, Aartjan T.F.
AU - Bigdeli, Tim B.
AU - Binder, Elisabeth B.
AU - Blackwood, Douglas H.R.
AU - Bryois, Julien
AU - Buttenschøn, Henriette N.
AU - Bybjerg-Grauholm, Jonas
AU - Cai, Na
AU - Castelao, Enrique
AU - Christensen, Jane varregaard
AU - Clarke, Toni Kim
AU - Coleman, Jonathan R.I.
AU - Colodro-Conde, Lucía
AU - Couvy-Duchesne, Baptiste
AU - Craddock, Nick
AU - Crawford, Gregory E.
AU - Davies, Gail
AU - Deary, Ian J.
AU - Degenhardt, Franziska
AU - Derks, Eske M.
AU - Direk, Nese
AU - Dolan, Conor V.
AU - Dunn, Erin C.
AU - Eley, Thalia C.
AU - Escott-Price, Valentina
AU - Kiadeh, Farnush Farhadi Hassan
AU - Finucane, Hilary K.
AU - Forstner, Andreas J.
AU - Frank, Josef
AU - Gaspar, Héléna A.
AU - Gill, Michael
AU - Goes, Fernando S.
AU - Gordon, Scott D.
AU - Grove, Jakob
AU - Hall, Lynsey S.
AU - Hansen, Christine Søholm
AU - Hansen, Thomas F.
AU - Herms, Stefan
AU - Hickie, Ian B.
AU - Hoffmann, Per
AU - Homuth, Georg
AU - Horn, Carsten
AU - Hottenga, Jouke Jan
AU - Hougaard, David M.
AU - Ising, Marcus
AU - Jansen, Rick
AU - Jorgenson, Eric
AU - Knowles, James A.
AU - Kohane, Isaac S.
AU - Kraft, Julia
AU - Kretzschmar, Warren W.
AU - Krogh, Jesper
AU - Kutalik, Zoltán
AU - Li, Yihan
AU - Lind, Penelope A.
AU - MacIntyre, Donald J.
AU - MacKinnon, Dean F.
AU - Maier, Robert M.
AU - Maier, Wolfgang
AU - Marchini, Jonathan
AU - Mbarek, Hamdi
AU - McGrath, Patrick
AU - McGuffin, Peter
AU - Medland, Sarah E.
AU - Mehta, Divya
AU - Middeldorp, Christel M.
AU - Mihailov, Evelin
AU - Milaneschi, Yuri
AU - Milani, Lili
AU - Mondimore, Francis M.
AU - Montgomery, Grant W.
AU - Mostafavi, Sara
AU - Mullins, Niamh
AU - Nauck, Matthias
AU - Ng, Bernard
AU - Nivard, Michel G.
AU - Nyholt, Dale R.
AU - O’Reilly, Paul F.
AU - Oskarsson, Hogni
AU - Owen, Michael J.
AU - Painter, Jodie N.
AU - Pedersen, Carsten Bøcker
AU - Pedersen, Marianne Giørtz
AU - Peterson, Roseann E.
AU - Pettersson, Erik
AU - Peyrot, Wouter J.
AU - Pistis, Giorgio
AU - Posthuma, Danielle
AU - Quiroz, Jorge A.
AU - Qvist, Per
AU - Rice, John P.
AU - Riley, Brien P.
AU - Rivera, Margarita
AU - Mirza, Saira Saeed
AU - Schoevers, Robert
AU - Schulte, Eva C.
AU - Shen, Ling
AU - Shi, Jianxin
AU - Shyn, Stanley I.
AU - Sigurdsson, Engilbert
AU - Sinnamon, Grant C.B.
AU - Smit, Johannes H.
AU - Smith, Daniel J.
AU - Stefansson, Hreinn
AU - Steinberg, Stacy
AU - Streit, Fabian
AU - Strohmaier, Jana
AU - Tansey, Katherine E.
AU - Teismann, Henning
AU - Teumer, Alexander
AU - Thompson, Wesley
AU - Thomson, Pippa A.
AU - Thorgeirsson, Thorgeir E.
AU - Traylor, Matthew
AU - Treutlein, Jens
AU - Trubetskoy, Vassily
AU - Uitterlinden, André G.
AU - Umbricht, Daniel
AU - Van der Auwera, Sandra
AU - van Hemert, Albert M.
AU - Viktorin, Alexander
AU - Visscher, Peter M.
AU - Wang, Yunpeng
AU - Webb, Bradley T.
AU - Weinsheimer, Shantel Marie
AU - Wellmann, Jürgen
AU - Willemsen, Gonneke
AU - Witt, Stephanie H.
AU - Wu, Yang
AU - Xi, Hualin S.
AU - Yang, Jian
AU - Zhang, Futao
AU - Arolt, Volker
AU - Baune, Bernhard T.
AU - Berger, Klaus
AU - Boomsma, Dorret I.
AU - Cichon, Sven
AU - Dannlowski, Udo
AU - de Geus, E. J.C.
AU - DePaulo, J. Raymond
AU - Domenici, Enrico
AU - Domschke, Katharina
AU - Esko, Tõnu
AU - Grabe, Hans J.
AU - Hamilton, Steven P.
AU - Hayward, Caroline
AU - Heath, Andrew C.
AU - Kendler, Kenneth S.
AU - Kloiber, Stefan
AU - Lewis, Glyn
AU - Li, Qingqin S.
AU - Lucae, Susanne
AU - Madden, Pamela A.F.
AU - Magnusson, Patrik K.
AU - Martin, Nicholas G.
AU - McIntosh, Andrew M.
AU - Metspalu, Andres
AU - Mors, Ole
AU - Mortensen, Preben Bo
AU - Müller-Myhsok, Bertram
AU - Nordentoft, Merete
AU - Nöthen, Markus M.
AU - O’Donovan, Michael C.
AU - Paciga, Sara A.
AU - Pedersen, Nancy L.
AU - Penninx, Brenda W.J.H.
AU - Perlis, Roy H.
AU - Porteous, David J.
AU - Potash, James B.
AU - Preisig, Martin
AU - Rietschel, Marcella
AU - Schaefer, Catherine
AU - Schulze, Thomas G.
AU - Smoller, Jordan W.
AU - Stefansson, Kari
AU - Tiemeier, Henning
AU - Uher, Rudolf
AU - Völzke, Henry
AU - Weissman, Myrna M.
AU - Werge, Thomas
AU - Lewis, Cathryn M.
AU - Levinson, Douglas F.
AU - Breen, Gerome
AU - Børglum, Anders D.
AU - Sullivan, Patrick F.
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
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.
UR - http://www.scopus.com/inward/record.url?scp=85081737215&partnerID=8YFLogxK
U2 - 10.1038/s41380-020-0689-5
DO - 10.1038/s41380-020-0689-5
M3 - Article
C2 - 32203155
AN - SCOPUS:85081737215
VL - 26
SP - 2457
EP - 2470
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 6
ER -