Regional gene expression signatures are associated with sex-specific functional connectivity changes in depression

Aleksandr Talishinsky, Jonathan Downar, Petra E Vértes, Jakob Seidlitz, Katharine Dunlop, Charles J Lynch, Heather Whalley, Andrew McIntosh, Fidel Vila-Rodriguez, Zafiris J Daskalakis, Daniel M Blumberger, Conor Liston

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The neural substrates of depression may differ in men and women, but the underlying mechanisms are incompletely understood. Here, we show that depression is associated with sex-specific patterns of abnormal functional connectivity in the default mode network and in five regions of interest with sexually dimorphic transcriptional effects. Regional differences in gene expression in two independent datasets explained the neuroanatomical distribution of abnormal connectivity. These gene sets varied by sex and were strongly enriched for genes implicated in depression, synapse function, immune signaling, and neurodevelopment. In an independent sample, we confirmed the prediction that individual differences in default mode network connectivity are explained by inferred brain expression levels for six depression-related genes, including PCDH8, a brain-specific protocadherin integral membrane protein implicated in activity-related synaptic reorganization. Together, our results delineate both shared and sex-specific changes in the organization of depression-related functional networks, with implications for biomarker development and fMRI-guided therapeutic neuromodulation.

Original languageEnglish
Pages (from-to)5692
JournalNature Communications
Issue number1
Early online date28 Sept 2022
Publication statusE-pub ahead of print - 28 Sept 2022

Keywords / Materials (for Non-textual outputs)

  • Brain/diagnostic imaging
  • Brain Mapping/methods
  • Depression/genetics
  • Female
  • Humans
  • Magnetic Resonance Imaging/methods
  • Male
  • Neural Pathways
  • Protocadherins
  • Transcriptome


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