Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach Pérez-Gutiérrez, Ana María Carmona, Rosario Loucera, Carlos Cervilla Ballesteros, Jorge Antonio Gutiérrez Martínez, Blanca Molina Rivas, Esther López-López, Daniel Pérez-Florido, Javier Zarza Rebollo, Juan Antonio López Isac, Elena Dopazo, Joaquín Martínez González, Luis Javier Rivera Sánchez, Margarita This study was partially funded by Consejería de Salud, Junta de Andalucía (PI322-2009), Consejería de Innovación, Proyecto de Excelencia (CTS-2010-6682), Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (PI18/00238 and PI23/00201), FEDER/Junta de Andalucía (B-CTS-256-UGR20), the Marie Curie research Grants Scheme (FP7-626235) and by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (22514). AMPG was supported by a grant from the Ministry of Economy and Competitiveness and Institute of Health Carlos III (FI19/00228). ELI received financial support from the Spanish Ministry of Science and Innovation Juan de la Cierva Incorporación Program (grant code IJC2019-040080-I/AEI/10.13039/501100011033) and Ramon y Cajal Program (RYC2021-034816-I). RC was supported by a Postdoctoral Grant RH-0052-2021 from Junta de Andalucía and co-funded by the European Union, European Social Fund (FSE) 2014–2020. Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders. 2025-01-23T09:26:30Z 2025-01-23T09:26:30Z 2024-05-28 journal article Pérez-Gutiérrez, A.M., Carmona, R., Loucera, C. et al. Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach. Mol Psychiatry 29, 3553–3566 (2024). https://doi.org/10.1038/s41380-024-02609-2 https://hdl.handle.net/10481/100102 10.1038/s41380-024-02609-2 eng info:eu-repo/grantAgreement/EC/FP7/626235 http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License Springer Nature