Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study
Authors: Coombes Brandon J. , Millischer Vincent , Batzler Anthony , Larrabee Beth , Hou Liping , Papiol Sergi , Heilbronner Urs , Adli Mazda , Akiyama Kazufumi , Akula Nirmala , Amare Azmeraw T. , Ardau Raffaella , Arias Barbara , Aubry Jean-Michel , Backlund Lena , Bauer Michael , Baune Bernhard T. , Bellivier Frank , Benabarre Antoni , Bengesser Susanne , Bhattacharjee Abesh Kumar , Cervantes Pablo , Chen Hsi-Chung , Chillotti Caterina , Cichon Sven , Clark Scott R. , Colom Francesc , Cruceanu Cristiana , Czerski Piotr M. , Dalkner Nina , Degenhardt Franziska , Del Zompo Maria , DePaulo J. Raymond , Étain Bruno , Falkai Peter , Ferensztajn-Rochowiak Ewa , Forstner Andreas J. , Frisen Louise , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hauser Joanna , Herms Stefan , Hoffmann Per , Jamain Stephane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kato Tadafumi , Kelsoe John R. , Kittel-Schneider Sarah , König Barbara , Kuo Po-Hsiu , Kusumi Ichiro , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , Maj Mario , Manchia Mirko , Martinsson Lina , McCarthy Michael J. , McElroy Susan L. , Mitchell Philip B. , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Nöthen Markus M. , Novák Tomas , O’Donovan Claire , Osby Urban , Ozaki Norio , Pfennig Andrea , Pisanu Claudia , Potash James B. , Reif Andreas , Reininghaus Eva , Rietschel Marcella , Rouleau Guy A. , Rybakowski Janusz K. , Schalling Martin , Schofield Peter R. , Schubert Klaus Oliver , Schweizer Barbara W. , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D. , Shimoda Katzutaka , Simhandl Christian , Slaney Claire M. , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Tortorella Alfonso , Turecki Gustavo , Vieta Eduard , Witt Stephanie H. , Zandi Peter P. , Fullerton Janice M. , Alda Martin , Frye Mark A. , Schulze Thomas G. , McMahon Francis J. , Biernacka Joanna M. 
Published: November 2021

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.