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Exploring the genetics of lithium response in bipolar disorders.

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

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=2,064) 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.

PMID: 38077040

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