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Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder

Abstract

The etiopathology of bipolar disorder is largely unknown. We collected cerebrospinal fluid (CSF) samples from two independent case-control cohorts (total n = 351) to identify proteins associated with bipolar disorder. A panel of 92 proteins targeted towards central nervous system processes identified two proteins that replicated across the cohorts: the CSF concentrations of testican-1 were lower, and the CSF concentrations of C-type lectin domain family 1 member B (CLEC1B) were higher, in cases than controls. In a restricted subgroup analysis, we compared only bipolar type 1 with controls and identified two additional proteins that replicated in both cohorts: draxin and tumor necrosis factor receptor superfamily member 21 (TNFRSF21), both lower in cases than controls. This analysis additionally revealed several proteins significantly associated with bipolar type 1 in one cohort, falling just short of replicated statistical significance in the other (tenascin-R, disintegrin and metalloproteinase domain-containing protein 23, cell adhesion molecule 3, RGM domain family member B, plexin-B1, and brorin). Next, we conducted genome-wide association analyses of the case-control-associated proteins. In these analyses, we found associations with the voltage-gated calcium channel subunit CACNG4, and the lipid-droplet-associated gene PLIN5 with CSF concentrations of TNFRSF21 and CLEC1B, respectively. The reported proteins are involved in neuronal cell-cell and cell-matrix interactions, particularly in the developing brain, and in pathways of importance for lithium’s mechanism of action. In summary, we report four novel CSF protein associations with bipolar disorder that replicated in two independent case-control cohorts, shedding new light on the central nervous system processes implicated in bipolar disorder.

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Fig. 1: Forrest plot showing odds ratio (OR) and 95% confidence interval (CI) from case-control association tests.
Fig. 2: Genetic association analyses of the cerebrospinal fluid (CSF) concentrations of tumor necrosis factor receptor superfamily member 21 (TNFRSF21) and C-type lectin family 1 member B (CLEC1B).

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Acknowledgements

This study was a part of the St. Göran bipolar project. We are deeply grateful to the patients and controls participating in this study. We also thank staff at the bipolar outpatient clinics in Stockholm (Norra Stockholms Psykiatri) and Gothenburg (Bipolärmottagningen), including study nurses Martina Wennberg, Lena Lundberg, Agneta Carlswärd-Kjellin, Annika Blom, Benita Gezelius, Therese Thuresson, and Stefanie Unger, as well as data managers Haydeh Olofsson and Mathias Kardell. Yngve Hallström and Aurimantas Pelanis performed the lumbar punctures. The St. Göran bipolar study was funded by grants from the Swedish foundation for Strategic Research (#KF10-0039), the Swedish Medical Research Council (#2018-02653), the Swedish Brain foundation (#FO2020-0261), and by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (#ALF 20170019, #ALFGBG-716801). Further support was provided by the Swedish Research Council for Health, Working Life and Welfare, Åhlen’s foundation, Magnus Bergvall’s foundation, the Lars Hierta Memorial Foundation, and Märta Lundqvist’s foundation. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, the Swedish Brain foundation (#FO2019-0228), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL.

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ML, JHL, JJ, and EP concepted the study. ML, AP, and TS collected the samples. AG and AI analyzed the data. LJ, EP, and HZ contributed to the interpretation. AG and ML wrote the manuscript. All authors revised and approved the manuscript.

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Correspondence to Andreas Göteson.

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ML declares that he has received lecture honoraria from Lundbeck pharmaceutical. JJ declares that he was an employee at AstraZeneca pharmaceutical 2017-2019, and JHL declares that she is a current employee at AstraZeneca pharmaceutical. HZ has served at scientific advisory boards for Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Other authors declare no conflict of interest.

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Göteson, A., Isgren, A., Jonsson, L. et al. Cerebrospinal fluid proteomics targeted for central nervous system processes in bipolar disorder. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01236-5

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