Abstract
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with major depressive disorder (MDD), yet the complex gene networks underpinning this polygenic risk remain largely uncharacterised. Here, we elucidate the neurobiological mechanisms of MDD by analyzing co-expression networks of 94 risk genes in the human prefrontal cortex. By linking these networks to individual symptoms, we identify the FADS1 (fatty acid desaturase 1) network as a central integrator across symptom clusters. We find that the FADS1 network functions primarily in astrocytes to regulate fatty acid metabolism and influence oligodendrocyte-related cell states. Furthermore, we identify FGF2 as a synaptic effector of this pathway and highlight PPARα (peroxisome proliferator-activated receptor alpha) as a putative therapeutic target. These results establish astrocyte fatty acid metabolism as a critical mechanistic contributor to MDD and a promising avenue for treatment.
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Data availability
Co-expression networks are available from https://zenodo.org/records/10181579. GWAS summary statistics are available from the PGC consortium website: https://pgc.unc.edu/for-researchers/download-results/. GTEx data are available through the online portal or through dbGAP for protected datasets. See https://www.gtexportal.org/home/datasets for more information. The MDD summary statistics were downloaded from iPSYCH as described in the original publication15 (https://ipsych.dk/en/research/downloads/). Hi-C data from the DLPFC16 were obtained from https://zenodo.org/record/6382668#.Y9PSG3bMJPY. Single nucleus RNA seq data from Nagy et al. and Maitra et al. (accession numbers GSE144136 and GSE213982 respectively). GnomAD data were downloaded from https://gnomad.broadinstitute.org/downloads.
Code availability
Code used for co-expression was adapted from Kim et al.9. All code used in this study is available at https://zenodo.org/records/10181579.
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Acknowledgements
This work was funded through a Hope for Depression Research Foundation grant to MJM. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from: the GTEx Portal or dbGaP accession number phs000424.v9.p2. Schematics were created with BioRender.com.
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E.F. conceived the study, with input from M.J.M., E.F., N.O.T., and I.P. analysed the data. E.F. interpreted the data and wrote the manuscript with input from E.J.N, G.T., C.N., and M.J.M. All authors approved the final version of the manuscript.
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Fitzgerald, E., O’Toole, N., Pokhvisneva, I. et al. Astrocyte fatty acid metabolism as a driver of risk for major depressive disorder. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71542-5
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DOI: https://doi.org/10.1038/s41467-026-71542-5
