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[Preprint]. 2023 Dec 2:rs.3.rs-3677630.
doi: 10.21203/rs.3.rs-3677630/v1.

Exploring the genetics of lithium response in bipolar disorders

Marisol Herrera-Rivero  1 , Mazda Adli  2 , Kazufumi Akiyama  3 , Nirmala Akula  4 , Azmeraw T Amare  5 , Raffaella Ardau  6 , Bárbara Arias  7 , Jean-Michel Aubry  8 , Lena Backlund  9 , Frank Bellivier  10 , Antonio Benabarre  11 , Susanne Bengesser  12 , Abesh Kumar Bhattacharjee  13 , Joanna M Biernacka  14 , Armin Birner  12 , Micah Cearns  5 , Pablo Cervantes  15 , Hsi-Chung Chen  16 , Caterina Chillotti  6 , Sven Cichon  17 , Scott R Clark  5 , Francesc Colom  18 , Cristiana Cruceanu  19 , Piotr M Czerski  20 , Nina Dalkner  12 , Franziska Degenhardt  21 , Maria Del Zompo  22 , J Raymond DePaulo  23 , Bruno Etain  10 , Peter Falkai  24 , Ewa Ferensztajn-Rochowiak  20 , Andreas J Forstner  21 , Josef Frank  25 , Louise Frisén  9 , Mark A Frye  14 , Janice M Fullerton  26 , Carla Gallo  27 , Sébastien Gard  28 , Julie S Garnham  29 , Fernando S Goes  23 , Maria Grigoroiu-Serbanescu  30 , Paul Grof  31 , Ryota Hashimoto  32 , Roland Hasler  8 , Joanna Hauser  20 , Urs Heilbronner  24 , Stefan Herms  21 , Per Hoffmann  21 , Liping Hou  4 , Yi-Hsiang Hsu  33 , Stéphane Jamain  34 , Esther Jiménez  11 , Jean-Pierre Kahn  35 , Layla Kassem  4 , Tadafumi Kato  36 , John Kelsoe  13 , Sarah Kittel-Schneider  37 , Po-Hsiu Kuo  16 , Ichiro Kusumi  38 , Barbara König  39 , Gonzalo Laje  4 , Mikael Landén  40 , Catharina Lavebratt  9 , Marion Leboyer  34 , Susan G Leckband  41 , Mario Maj  42 , Mirko Manchia  22 , Cynthia Marie-Claire  10 , Lina Martinsson  9 , Michael J McCarthy  13 , Susan L McElroy  43 , Vincent Millischer  9 , Marina Mitjans  44 , Francis M Mondimore  23 , Palmiero Monteleone  45 , Caroline M Nievergelt  13 , Tomas Novák  32 , Markus M Nöthen  21 , Claire O'Donovan  29 , Norio Ozaki  46 , Sergi Papiol  24 , Andrea Pfennig  47 , Claudia Pisanu  22 , James B Potash  23 , Andreas Reif  48 , Eva Reininghaus  12 , Hélène Richard-Lepouriel  8 , Gloria Roberts  26 , Guy A Rouleau  19 , Janusz K Rybakowski  20 , Martin Schalling  9 , Peter R Schofield  26 , Klaus Oliver Schubert  5 , Eva C Schulte  24 , Barbara W Schweizer  23 , Giovanni Severino  22 , Tatyana Shekhtman  13 , Paul D Shilling  13 , Katzutaka Shimoda  3 , Christian Simhandl  49 , Claire M Slaney  29 , Alessio Squassina  22 , Thomas Stamm  2 , Pavla Stopkova  32 , Fabian Streit  25 , Fasil Tekola-Ayele  50 , Anbupalam Thalamuthu  26 , Alfonso Tortorella  51 , Gustavo Turecki  19 , Julia Veeh  48 , Eduard Vieta  11 , Biju Viswanath  52 , Stephanie H Witt  25 , Peter P Zandi  23 , Martin Alda  29 , Michael Bauer  47 , Francis J McMahon  4 , Philip B Mitchell  26 , Marcella Rietschel  25 , Thomas G Schulze  24 , Bernhard T Baune  1
Affiliations

Exploring the genetics of lithium response in bipolar disorders

Marisol Herrera-Rivero et al. Res Sq. .

Update in

  • Exploring the genetics of lithium response in bipolar disorders.
    Herrera-Rivero M, Adli M, Akiyama K, Akula N, Amare AT, Ardau R, Arias B, Aubry JM, Backlund L, Bellivier F, Benabarre A, Bengesser S, Bhattacharjee AK, Biernacka JM, Birner A, Cearns M, Cervantes P, Chen HC, Chillotti C, Cichon S, Clark SR, Colom F, Cruceanu C, Czerski PM, Dalkner N, Degenhardt F, Del Zompo M, DePaulo JR, Etain B, Falkai P, Ferensztajn-Rochowiak E, Forstner AJ, Frank J, Frisén L, Frye MA, Fullerton JM, Gallo C, Gard S, Garnham JS, Goes FS, Grigoroiu-Serbanescu M, Grof P, Hashimoto R, Hasler R, Hauser J, Heilbronner U, Herms S, Hoffmann P, Hou L, Hsu YH, Jamain S, Jiménez E, Kahn JP, Kassem L, Kato T, Kelsoe J, Kittel-Schneider S, Kuo PH, Kusumi I, König B, Laje G, Landén M, Lavebratt C, Leboyer M, Leckband SG, Maj M, Manchia M, Marie-Claire C, Martinsson L, McCarthy MJ, McElroy SL, Millischer V, Mitjans M, Mondimore FM, Monteleone P, Nievergelt CM, Novák T, Nöthen MM, O'Donovan C, Ozaki N, Papiol S, Pfennig A, Pisanu C, Potash JB, Reif A, Reininghaus E, Richard-Lepouriel H, Roberts G, Rouleau GA, Rybakowski JK, Schalling M, Schofield PR, Schubert KO, Schulte EC, Schweizer BW, Severino G, Shekhtman T, Shilling PD, Shimoda K, Simhandl C, Slaney CM, Squassina A, Sta… See abstract for full author list ➔ Herrera-Rivero M, et al. Int J Bipolar Disord. 2024 Jun 12;12(1):20. doi: 10.1186/s40345-024-00341-y. Int J Bipolar Disord. 2024. PMID: 38865039 Free PMC article.

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=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.

Keywords: Bipolar disorder; comorbidity; genetics; lithium treatment; psychiatric symptoms.

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Conflict of interest statement

Competing interests Eduard Vieta has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbvie, Almirall, Allergan, Angelini, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GH Research, Glaxo-Smith-Kline, Janssen, Lundbeck, Orion, Otsuka, Pfizer, Roche, Rovi, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Spanish Ministry of Science and Innovation (CIBERSAM), the Stanley Medical Research Institute and Viatris. Michael Bauer has received grants from the Deutsche Forschungsgemeinschaft (DFG), and Bundesministeriums für Bildung und Forschung (BMBF), and served as consultant, advisor or CME speaker for the following entities: Allergan, Aristo, Janssen, Lilly, Lundbeck, neuraxpharm, Otsuka, Sandoz, Servier and Sunovion outside the submitted work. Sarah Kittel-Schneider has received grants and served as consultant, advisor or speaker for the following entities: Medice Arzneimittel Pütter GmbH and Takeda. Bernhard Baune has received grants and served as consultant, advisor or CME speaker for the following entities: AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, Otsuka, Servier, the National Health and Medical Research Council, the Fay Fuller Foundation, the James and Diana Ramsay Foundation. Tadafumi Kato received honoraria for lectures, manuscripts, and/or consultancy, from Kyowa Hakko Kirin Co, Ltd, Eli Lilly Japan K.K., Otsuka Pharmaceutical Co, Ltd, GlaxoSmithKline K.K., Taisho Toyama Pharmaceutical Co, Ltd, Dainippon Sumitomo Pharma Co, Ltd, Meiji Seika Pharma Co, Ltd, Pfizer Japan Inc., Mochida Pharmaceutical Co, Ltd, Shionogi & Co, Ltd, Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, Astellas Pharma Inc, Wako Pure Chemical Industries, Ltd, Wiley Publishing Japan, Nippon Boehringer Ingelheim Co Ltd, Kanae Foundation for the Promotion of Medical Science, MSD K.K., Kyowa Pharmaceutical Industry Co, Ltd and Takeda Pharmaceutical Co, Ltd. Tadafumi Kato also received a research grant from Takeda Pharmaceutical Co, Ltd. Peter Falkai has received grants and served as consultant, advisor or CME speaker for the following entities Abbott, GlaxoSmithKline, Janssen, Essex, Lundbeck, Otsuka, Gedeon Richter, Servier and Takeda as well as the German Ministry of Science and the German Ministry of Health. Eva Reininghaus has received grants and served as consultant, advisor or CME speaker for the following entities: Janssen and Institut Allergosan. Mikael Landén has received lecture honoraria from Lundbeck. Kazufumi Akiyama has received consulting honoraria from Taisho Toyama Pharmaceutical Co, Ltd. Scott Clark has received grants, or data and served as consultant, advisor or CME speaker for the following entities: Otsuka Austalia, Lundbeck Australia, Janssen-Cilag Australia, Servier Australia,Viatris. Bruno Etain received honoraria from Sanofi Aventis. The rest of authors have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Links between phenotypes and Li responses in ConLiGen. A) Association test results between total Alda scores and psychiatric symptoms. Shown are the nominal p-values (−log10) and z-values (effect) obtained from robust linear/logistic regression models. B) Correlation test results between total Alda scores and PGSs for comorbid conditions. Shown are the nominal p-values (−log10) and correlation coefficients (effect) obtained from partial correlation models using the Spearman method.
Figure 2
Figure 2
Visual integration of nominal findings for Li response genes. Shapes depict the diagnostic group analyzed while colors refer to the phenotypes nominally associated with the gene in our analyses, except for the blue color, which localized even the genes not analyzed in this study that were reported by Amare et al., 2023 as contributors to Li response in ConLiGen.
See this image and copyright information in PMC

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