Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study
Brandon J. Coombes, Vincent Millischer, Anthony Batzler, Beth R. Larrabee, Liping Hou, Sergi Papiol, Urs Heilbronner, Mazda Adli, Kazufumi Akiyama, Nirmala Akula, Azmeraw T. Amare, Raffaella Ardau, Bárbara Arias, Jean‐Michel Aubry, Lena Backlund, Michael Bauer, Bernhard T. Baune, Frank Bellivier, Antoni Benabarre, Susanne Bengesser, Abesh Kumar Bhattacharjee, Pablo Cervantes, Hsi‐Chung Chen, Caterina Chillotti, Sven Cichon, Scott R. Clark, Francesc Colom, Cristiana Cruceanu, Piotr M. Czerski, Nina Dalkner, Franziska Degenhardt, Maria Del Zompo, J. Raymond DePaulo, Bruno Étain, Peter Falkai, Ewa Ferensztajn‐Rochowiak, Andreas J. Forstner, Louise Frisén, Sébastien Gard, Julie Garnham, Fernando S. Goes, Maria Grigoroiu‐Serbânescu, Paul Grof, Ryota Hashimoto, Joanna Hauser, Stefan Herms, Per Hoffmann, Stéphane Jamain, Esther Jiménez, Jean‐Pierre Kahn, Layla Kassem, Tadafumi Kato, John R. Kelsoe, Sarah Kittel‐Schneider, Barbara König, Po‐Hsiu Kuo, Ichiro Kusumi, Gonzalo Laje, Mikael Landén, Catharina Lavebratt, Marion Leboyer, Susan G. Leckband, Mario Maj, Mirko Manchia, Lina Martinsson, Michael J. McCarthy, Susan L. McElroy, Philip B. Mitchell, Marina Mitjans, Francis M. Mondimore, Palmiero Monteleone, Caroline M. Nievergelt, Markus M. Nöthen, Tomáš Novák, Claire O’Donovan, Urban Ösby, Norio Ozaki, Andrea Pfennig, Claudia Pisanu, James B. Potash, Andreas Reif, Eva Z. Reininghaus, Marcella Rietschel, Guy A. Rouleau, Janusz Rybakowski, Martin Schalling, Peter R. Schofield, Klaus Oliver Schubert, Barbara Schweizer, Giovanni Severino, Tatyana Shekhtman, Paul D. Shilling, Katzutaka Shimoda, Christian Simhandl, Claire Slaney, Alessio Squassina, Thomas Stamm, Pavla Stopková, Alfonso Tortorella, Gustavo Turecki
Abstract
Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (<i>N</i> = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using <i>lassosum</i> and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = −0.14; 95% confidence interval [CI]: −0.24 to −0.03; <i>p</i> value = 0.010) and MDD (β = −0.16; 95% CI: −0.27 to −0.04; <i>p</i> value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34–1.93; <i>p</i> value = 2e−7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.