Exploring the genetics of lithium response in bipolar disorders
Authors: Herrera-Rivero Marisol , Adli Mazda , Akiyama Kazufumi , Akula Nirmala , Amare Azmeraw T. , Ardau Raffaella , Arias Bárbara , Aubry Jean-Michel , Backlund Lena , Bellivier Frank , Benabarre Antonio , Bengesser Susanne , Bhattacharjee Abesh Kumar , Biernacka Joanna M. , Birner Armin , Cearns Micah , 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 , Etain Bruno , Falkai Peter , Ferensztajn-Rochowiak Ewa , Forstner Andreas J. , Frank Josef , Frisén Louise , Frye Mark A. , Fullerton Janice M. , Gallo Carla , Gard Sébastien , Garnham Julie S. , Goes Fernando S. , Grigoroiu-Serbanescu Maria , Grof Paul , Hashimoto Ryota , Hasler Roland , Hauser Joanna , Heilbronner Urs , Herms Stefan , Hoffmann Per , Hou Liping , Hsu Yi-Hsiang , Jamain Stephane , Jiménez Esther , Kahn Jean-Pierre , Kassem Layla , Kato Tadafumi , Kelsoe John , Kittel-Schneider Sarah , Kuo Po-Hsiu , Kusumi Ichiro , König Barbara , Laje Gonzalo , Landén Mikael , Lavebratt Catharina , Leboyer Marion , Leckband Susan G. , Maj Mario , Manchia Mirko , Marie-Claire Cynthia , Martinsson Lina , McCarthy Michael J. , McElroy Susan L. , Millischer Vincent , Mitjans Marina , Mondimore Francis M. , Monteleone Palmiero , Nievergelt Caroline M. , Novák Tomas , Nöthen Markus M. , O’Donovan Claire , Ozaki Norio , Papiol Sergi , Pfennig Andrea , Pisanu Claudia , Potash James B. , Reif Andreas , Reininghaus Eva , Richard-Lepouriel Hélène , Roberts Gloria , Rouleau Guy A. , Rybakowski Janusz K. , Schalling Martin , Schofield Peter R. , Schubert Klaus Oliver , Schulte Eva C. , Schweizer Barbara W. , Severino Giovanni , Shekhtman Tatyana , Shilling Paul D. , Shimoda Katzutaka , Simhandl Christian , Slaney Claire M. , Squassina Alessio , Stamm Thomas , Stopkova Pavla , Streit Fabian , Tekola-Ayele Fasil , Thalamuthu Anbupalam , Tortorella Alfonso , Turecki Gustavo , Veeh Julia , Vieta Eduard , Viswanath Biju , Witt Stephanie H. , Zandi Peter P. , Alda Martin , Bauer Michael , McMahon Francis J. , Mitchell Philip B. , Rietschel Marcella , Schulze Thomas G. , Baune Bernhard T. 
Published: June 2024

Abstract
Background
Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II.

Results
We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism.

Conclusions
Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.