Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder

Amare, Azmeraw T.; Thalamuthu, Anbupalam; Schubert, Klaus Oliver; Fullerton, Janice M.; Ahmed, Muktar Beshir; Hartmann, Simon; Papiol, Sergi; Heilbronner, Urs; Degenhardt, Franziska; Tekola‐Ayele, Fasil; Hou, Liping; Hsu, Yi‐Hsiang; Shekhtman, Tatyana; Adli, Mazda; Akula, Nirmala; Akiyama, Kazufumi; Ardau, Raffaella; Arias, Bárbara; Aubry, Jean‐Michel; Backlund, Lena; Bhattacharjee, Abesh Kumar; Bellivier, Frank; Benabarre, Antoni; Bengesser, Susanne; Biernacka, Joanna M.; Birner, Armin; Marie-Claire, Cynthia; Cervantes, Pablo; Chen, Hsi‐Chung; Chillotti, Caterina; Cichon, Sven; Cruceanu, Cristiana; Czerski, Piotr M.; Dalkner, Nina; Zompo, Maria Del; DePaulo, J. Raymond; Étain, Bruno; Jamain, Stéphane; Falkai, Peter; Forstner, Andreas J.; Frisén, Louise; Frye, Mark A.; Gard, Sébastien; Garnham, Julie; Goes, Fernando S.; Grigoroiu‐Serbanescu, Maria; Fallgatter, Andreas J.; Stegmaier, Sophia; Ethofer, Thomas; Biere, Silvia; Petrova, Kristiyana; Schuster, Ceylan; Adorjan, Kristina; Budde, Monika; Heilbronner, Maria; Kálmán, Jánoš; Kohshour, Mojtaba Oraki; Reich‐Erkelenz, Daniela; Schaupp, Sabrina K.; Schulte, Eva C.; Senner, Fanny; Vogl, Thomas; Anghelescu, Ion‐George; Arolt, Volker; Dannlowski, Udo; Dietrich, Detlef E.; Figge, Christian; Jäger, Markus; Lang, Fabian; Juckel, Georg; Spitzer, Carsten; Reimer, Jens; Schmauß, Max; Schmitt, Andrea; Konrad, Carsten; Hagen, Martin von; Wiltfang, Jens; Zimmermann, Jörg; Andlauer, Till F. M.; Fischer, André; Bermpohl, Felix; Kraft, Vivien; Matura, Silke; Gryaznova, Anna; Falkenberg, Irina; Yildiz, Cüneyt; Kircher, Tilo; Schmidt, Julia; Koch, Marius; Gade, Katrin; Trost, Sarah; Haußleiter, Ida Sybille; Lambert, Martin; Rohenkohl, Anja; Grof, Paul; Hashimoto, Ryota; Twarowska-Hauser, Joanna; Herms, Stefan; Hoffmann, Per; Jiménez, Esther; Kahn, Jean‐Pierre; Kassem, Layla; Kuo, Po-Hsiu; Kato, Takeshi; Kelsoe, John R.; Kittel‐Schneider, Sarah; Ferensztajn‐Rochowiak, Ewa; König, Barbara; Kusumi, Ichiro; Laje, Gonzalo; Landén, Mikael; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; Tortorella, Alfonso; Manchia, Mirko; Martinsson, Lina; McCarthy, Michael J.; McElroy, Susan L.; Colom, Francesc; Mitjans, Marina; Mondimore, Francis M.; Monteleone, Palmiero; Nievergelt, Caroline M.; Nöthen, Markus M.; Novák, Tomáš; O′Donovan, Claire; Ozaki, Norio; Pfennig, Andrea; Pisanu, Claudia; Potash, James B.; Reif, Andreas; Reininghaus, Eva; Rouleau, Guy A.; Rybakowski, Janusz; Schalling, Martin; Schofield, Peter R.; Schweizer, Barbara; Severino, Giovanni; Shilling, Paul D.; Shimoda, Katzutaka; Simhandl, Christian; Slaney, Claire; Squassina, Alessio; Stamm, Thomas; Stopková, Pavla; Maj, Mario; Turecki, Gustavo; Vieta, Eduard; Veeh, Julia; Witt, Stephanie H.; Wright, Adam; Zandi, Peter P.; Mitchell, Philip B.; Bauer, Michael; Alda, Martin; Rietschel, Marcella; McMahon, Francis J.; Schulze, Thomas G.; Millischer, Vincent; Clark, Scott; Baune, Bernhard T.

doi:10.21203/rs.3.rs-2580252/v1

Cited by 3 publications

(2 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nevertheless, lithium is not consistently effective, and only approximately every third patient shows a favorable responsiveness. Prediction biomarkers such as polygenic scores should be identified, since they might be able to predict a more severe course of BD and could also establish individual treatment options [101]. Chronotype at baseline was associated with lithium response in BP I patients, and stronger morningness was favorable in the long run.…”

Section: Treatmentmentioning

confidence: 99%

“…A positive lithium response is predictable through GWAS, in which non-responders showed a longer circadian period and a lower amplitude of circadian rhythm [102]. Recently, a respective polygenic score for lithium treatment response (Li+PGS) in patients with BD has been developed [101]. Lithium seems to exert period shortening/shifting effects and trait-like differences in cellular rhythms that might influence its effectiveness and the patient's response [102].…”

Section: Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Bipolar Chronobiology in Men and Mice: A Narrative Review

Freund

Haussleiter

2023

Brain Sciences

View full text Add to dashboard Cite

In patients with bipolar disorder, we do not only see a cycling of mood episodes, but also a shift in circadian rhythm. In the present overview, the circadian rhythm, the “internal clock”, and their disruptions are briefly described. In addition, influences on circadian rhythms such as sleep, genetics, and environment are discussed. This description is conducted with a translational focus covering human patients as well as animal models. Concluding the current knowledge on chronobiology and bipolar disorder, implications for specificity and the course of bipolar disorder and treatment options are given at the end of this article. Taken together, circadian rhythm disruption and bipolar disorder are strongly correlated; the exact causation, however, is still unclear.

show abstract

Section: Treatmentmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

Bipolar Chronobiology in Men and Mice: A Narrative Review

Freund

Haussleiter

2023

Brain Sciences

View full text Add to dashboard Cite

show abstract

Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth

Jiang,

Zai,

Kennedy

et al. 2023

Transl Psychiatry

View full text Add to dashboard Cite

There is a gap in knowledge regarding the polygenic underpinnings of brain anomalies observed in youth bipolar disorder (BD). This study examined the association of a polygenic risk score for BD (BD-PRS) with grey matter structure and white matter integrity in youth with and without BD. 113 participants were included in the analyses, including 78 participants with both T1-weighted and diffusion-weighted MRI images, 32 participants with T1-weighted images only, and 3 participants with diffusion-weighted images only. BD-PRS was calculated using PRS-CS-auto and was based on independent adult genome-wide summary statistics. Vertex- and voxel-wise analyses examined the associations of BD-PRS with grey matter metrics (cortical volume [CV], cortical surface area [CSA], cortical thickness [CTh]) and fractional anisotropy [FA] in the combined sample, and separately in BD and HC. In the combined sample of participants with T1-weighted images (n = 110, 66 BD, 44 HC), higher BD-PRS was associated with smaller grey matter metrics in frontal and temporal regions. In within-group analyses, higher BD-PRS was associated with lower CTh of frontal, temporal, and fusiform gyrus in BD, and with lower CV and CSA of superior frontal gyrus in HC. In the combined sample of participants with diffusion-weighted images (n = 81, 49 BD, 32 HC), higher BD-PRS was associated with lower FA in widespread white matter regions. In summary, BD-PRS calculated based on adult genetic data was negatively associated with grey matter structure and FA in youth in regions implicated in BD, which may suggest neuroimaging markers of vulnerability to BD. Future longitudinal studies are needed to examine whether BD-PRS predicts neurodevelopmental changes in BD vs. HC and its interaction with course of illness and long-term medication use.

show abstract

Pharmacogenomic scores in psychiatry: systematic review of current evidence

Sharew,

Clark,

Schubert

et al. 2024

Transl Psychiatry

View full text Add to dashboard Cite

In the past two decades, significant progress has been made in the development of polygenic scores (PGSs). One specific application of PGSs is the development and potential use of pharmacogenomic- scores (PGx-scores) to identify patients who can benefit from a specific medication or are likely to experience side effects. This systematic review comprehensively evaluates published PGx-score studies in psychiatry and provides insights into their potential clinical use and avenues for future development. A systematic literature search was conducted across PubMed, EMBASE, and Web of Science databases until 22 August 2023. This review included fifty-three primary studies, of which the majority (69.8%) were conducted using samples of European ancestry. We found that over 90% of PGx-scores in psychiatry have been developed based on psychiatric and medical diagnoses or trait variants, rather than pharmacogenomic variants. Among these PGx-scores, the polygenic score for schizophrenia (PGSSCZ) has been most extensively studied in relation to its impact on treatment outcomes (32 publications). Twenty (62.5%) of these studies suggest that individuals with higher PGSSCZ have negative outcomes from psychotropic treatment — poorer treatment response, higher rates of treatment resistance, more antipsychotic-induced side effects, or more psychiatric hospitalizations, while the remaining studies did not find significant associations. Although PGx-scores alone accounted for at best 5.6% of the variance in treatment outcomes (in schizophrenia treatment resistance), together with clinical variables they explained up to 13.7% (in bipolar lithium response), suggesting that clinical translation might be achieved by including PGx-scores in multivariable models. In conclusion, our literature review found that there are still very few studies developing PGx-scores using pharmacogenomic variants. Research with larger and diverse populations is required to develop clinically relevant PGx-scores, using biology-informed and multi-phenotypic polygenic scoring approaches, as well as by integrating clinical variables with these scores to facilitate their translation to psychiatric practice.

show abstract

Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder

Cited by 3 publications

References 48 publications

Bipolar Chronobiology in Men and Mice: A Narrative Review

Bipolar Chronobiology in Men and Mice: A Narrative Review

Association of polygenic risk for bipolar disorder with grey matter structure and white matter integrity in youth

Pharmacogenomic scores in psychiatry: systematic review of current evidence

Contact Info

Product

Resources

About