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

Amare, A. T. et al. (2021) Association of polygenic score for major depression with response to lithium in patients with bipolar disorder. Molecular Psychiatry, 26(6), pp. 2457-2470. (doi: 10.1038/s41380-020-0689-5) (PMID:32203155)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel
Authors: Amare, A. T., Schubert, K. O., Hou, L., Clark, S. R., Papiol, S., Cearns, M., Heilbronner, U., Degenhardt, F., Tekola-Ayele, F., Hsu, Y.-H., Shekhtman, T., Adli, M., Akula, N., Akiyama, K., Ardau, R., Arias, B., Aubry, J.-M., Backlund, L., Bhattacharjee, A. K., Bellivier, F., Benabarre, A., Bengesser, S., Biernacka, J. M., Birner, A., Brichant-Petitjean, C., Cervantes, P., Chen, H.-C., Chillotti, C., Cichon, S., Cruceanu, C., Czerski, P. M., Dalkner, N., Dayer, A., Del Zompo, M., DePaulo, J. R., Étain, B., Jamain, S., Falkai, P., Forstner, A. J., Frisen, L., Frye, M. A., Fullerton, J. M., Gard, S., Garnham, J. S., Goes, F. S., Grigoroiu-Serbanescu, M., Grof, P., Hashimoto, R., Hauser, J., Herms, S., Hoffmann, P., Hofmann, A., Jiménez, E., Kahn, J.-P., Kassem, L., Kuo, P.-H., Kato, T., Kelsoe, J. R., Kittel-Schneider, S., Kliwicki, S., König, B., Kusumi, I., Laje, G., Landén, M., Lavebratt, C., Leboyer, M., Leckband, S. G., Tortorella, A., Manchia, M., Martinsson, L., McCarthy, M. J., McElroy, S. L., Colom, F., Mitjans, M., Mondimore, F. M., Monteleone, P., Nievergelt, C. M., Nöthen, M. M., Novák, T., O’Donovan, C., Ozaki, N., Ösby, U., Pfennig, A., Potash, J. B., Reif, A., Reininghaus, E., Rouleau, G. A., Rybakowski, J. K., Schalling, M., Schofield, P. R., Schweizer, B. W., Severino, G., Shilling, P. D., Shimoda, K., Simhandl, C., Slaney, C. M., Squassina, A., Stamm, T., Stopkova, P., Maj, M., Turecki, G., Vieta, E., Veeh, J., Witt, S. H., Wright, A., Zandi, P. P., Mitchell, P. B., Bauer, M., Alda, M., Rietschel, M., McMahon, F. J., Schulze, T. G., Baune, B. T., and Major Depressive Disorder Working Group of the PGC,
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Molecular Psychiatry
Publisher:Nature Research
ISSN (Online):1476-5578
Published Online:16 March 2020
Copyright Holders:Copyright © The Author(s), under exclusive licence to Springer Nature Limited 2020
First Published:First published in Molecular Psychiatry 26(6): 2457-2470
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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