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Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms

Molecular Psychiatry (2024)Cite this article

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Abstract

The DDR1 locus is associated with the diagnosis of schizophrenia and with processing speed in patients with schizophrenia and first-episode psychosis. Here, we investigated whether DDR1 variants are associated with bipolar disorder (BD) features. First, we performed a case‒control association study comparing DDR1 variants between patients with BD and healthy controls. Second, we performed linear regression analyses to assess the associations of DDR1 variants with neurocognitive domains and psychosocial functioning. Third, we conducted a mediation analysis to explore whether neurocognitive impairment mediated the association between DDR1 variants and psychosocial functioning in patients with BD. Finally, we studied the association between DDR1 variants and white matter microstructure. We did not find any statistically significant associations in the case‒control association study; however, we found that the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse neurocognitive performance in patients with BD with psychotic symptoms. In addition, the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse psychosocial functioning through processing speed. We did not find correlations between white matter microstructure abnormalities and the neurocognitive domains associated with the combined genotypes rs1264323AA-rs2267641AC/CC. Overall, the results suggest that DDR1 may be a marker of worse neurocognitive performance and psychosocial functioning in patients with BD, specifically those with psychotic symptoms.

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Fig. 1: SNPs genotyped and selected for association analyses.
Fig. 2: Association of the combined genotypes rs1264323AA-rs2267641AC/CC with neurocognitive performance.
Fig. 3: Effect of the combined genotypes rs1264323AA-rs2267641AC/CC on psychosocial functioning in patients with BD with psychotic symptoms.

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Acknowledgements

This study was supported by grants from the Brain and Behavior Research Foundation (2017 NARSAD Independent grant, #25811 to Eisabet V), Instituto de Salud Carlos III (Research Project PI15/00852 and PI18/00954 to Eisabet V, PI15/00283 to Eduard V and PI15/00277 to EC-R), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) (Intramural project grant to Eduard V) and Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR00444 and 2021SGR01065 to Eisabet V, 2017SGR01365 and 2021SGR01358 to Eduard V, 2017SGR01271 and 2021SGR01475 to EP-C). Selena Aranda received a predoctoral fellowship granted by the Instituto de Salud Carlos III (PFIS FI19/00268). EC-R was supported by the Swiss National Science Foundation and Ambizione grant PZ00P2_185814. The funding organizations played no role in the study design, data collection, analysis, or manuscript approval.

Author information

Authors and Affiliations

  1. Institut d’Investigació Sanitària Pere Virgili-CERCA, Reus, Spain

    Selena Aranda, Esteban Sepúlveda & Elisabet Vilella

  2. Hospital Universitari Institut Pere Mata, Reus, Spain

    Selena Aranda, Esteban Sepúlveda & Elisabet Vilella

  3. Universitat Rovira i Virgili, Reus, Spain

    Selena Aranda, Esteban Sepúlveda & Elisabet Vilella

  4. Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM)-Instituto de Salud Carlos III, Madrid, Spain

    Selena Aranda, Esther Jiménez, Erick J. Canales-Rodríguez, Norma Verdolini, Silvia Alonso, Esteban Sepúlveda, Julio Bobes, Pilar A. Sáiz, Paz García-Portilla, Jose M. Menchón, José M. Crespo, Ana González-Pinto, Víctor Pérez, Celso Arango, Julio Sanjuán, Edith Pomarol-Clotet, Eduard Vieta & Elisabet Vilella

  5. Bipolar and Depressive Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, Barcelona, Spain

    Esther Jiménez, Norma Verdolini, Silvia Alonso & Eduard Vieta

  6. Department of Psychiatry, University of the Basque Country (UPV-EHU), Vitoria-Gasteiz, Spain

    Esther Jiménez & Ana González-Pinto

  7. FIDMAG Germanes Hospitalàries Research Foundation, Sant Boi de Llobregat, Barcelona, Spain

    Erick J. Canales-Rodríguez, Norma Verdolini & Edith Pomarol-Clotet

  8. Signal Processing Laboratory (LTS5), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Erick J. Canales-Rodríguez

  9. Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain

    Antonio Julià & Sara Marsal

  10. Department of Psychiatry, Universidad de Oviedo, Oviedo, Spain

    Julio Bobes, Pilar A. Sáiz & Paz García-Portilla

  11. nstituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain

    Julio Bobes, Pilar A. Sáiz & Paz García-Portilla

  12. Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain

    Julio Bobes, Pilar A. Sáiz & Paz García-Portilla

  13. Servicio de Salud del Principado de Asturias (SESPA) Oviedo, Oviedo, Spain

    Julio Bobes, Pilar A. Sáiz & Paz García-Portilla

  14. Bellvitge Biomedical Research Institute-IDIBELL, Bellvitge University Hospital, Barcelona, Spain

    Jose M. Menchón & José M. Crespo

  15. Department of Clinical Sciences, University of Barcelona, Barcelona, Spain

    Jose M. Menchón & José M. Crespo

  16. Araba University Hospital, Bioaraba Research Institute, UPV/EHU, Vitoria-Gasteiz, Spain

    Ana González-Pinto

  17. Hospital de Mar. Mental Health Institute, Barcelona, Spain

    Víctor Pérez

  18. Neurosciences Research Unit, Hospital del Mar d’Investigacions Mèdiques, Barcelona, Spain

    Víctor Pérez

  19. Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain

    Víctor Pérez

  20. Institute of Psychiatry and Mental Health, Madrid, Spain

    Celso Arango

  21. Hospital General Universitario Gregorio Marañón, Madrid, Spain

    Celso Arango

  22. Universidad Complutense, Madrid, Spain

    Celso Arango

  23. La Fe University and Polytechnic Hospital, Valencia, Spain

    Pilar Sierra

  24. Department of Psychiatry, School of Medicine, University of Valencia, Valencia, Spain

    Pilar Sierra & Julio Sanjuán

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  1. Selena Aranda
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  2. Esther Jiménez
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  3. Erick J. Canales-Rodríguez
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  4. Norma Verdolini
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  6. Esteban Sepúlveda
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  16. Celso Arango
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  17. Pilar Sierra
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  19. Edith Pomarol-Clotet
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  20. Eduard Vieta
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  21. Elisabet Vilella
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Contributions

El. V, EP-C and Ed. V designed and directed the project. El. V and SA conceived and planned the study. EJ, NV, ES, AJ, SM, JB, PAS-M, PG-P, JMM, JMC, AG-P, VP, CA, PS and JS were involved in the patient assessment. SA performed the statistical analyses. EC-R conducted the neuroimaging study. SA and El. V took the lead in writing the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Elisabet Vilella.

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Competing interests

Eduard V has received grants and served as consultant, advisor, or CME speaker (unrelated to this work) for the following entities: AB-Biotics, Abbott, AbbVie, Angelini, Biogen, Compass, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Glaxo Smith-Kline, GH Research, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris. AGP has received grants and served as a consultant, advisor or CME speaker for the following entities: Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Sanofi-Aventis, Alter, Angelini, Exeltis, Novartis, Rovi, Takeda, the Spanish Ministry of Science and Innovation (CIBERSAM), the Ministry of Science (Carlos III Institute), the Basque Government, and the European Framework Program of Research. The other authors have no conflicts of interest to disclose. CA received support from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, and ERDF Funds from the European Commission, “A way of making Europe”, financed by the European Union - NextGenerationEU (PMP21/00051), PI19/01024, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement No.101034377), Project AIMS-2-TRIALS (Grant agreement No. 777394), Horizon Europe, the National Institute of Mental Health of the National Institutes of Health under Award Number 1U01MH124639–01 (Project ProNET) and Award Number 5P50MH115846–03 (project FEP-CAUSAL), Fundación Familia Alonso, and Fundación Alicia Koplowitz.

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Aranda, S., Jiménez, E., Canales-Rodríguez, E.J. et al. Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02480-1

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