Convergent molecular, cellular, and cortical neuroimaging signatures of major depressive disorder
Open Access
- 21 September 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (40), 25138-25149
- https://doi.org/10.1073/pnas.2008004117
Abstract
Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.Keywords
Funding Information
- HHS | NIH | National Institute of Mental Health (K01MH099232)
- HHS | NIH | National Institute of Mental Health (R01MH120080)
- National Science Foundation (DGE-1122492)
- Ministry of Education - Singapore (MOE2014-T2-2-016)
- National University of Singapore (DPRT/944/09/14)
- National University of Singapore (R185000271720)
- National University of Singapore (CBRG14nov007)
This publication has 105 references indexed in Scilit:
- Prevalence and Characteristics of Probable Major Depression and Bipolar Disorder within UK Biobank: Cross-Sectional Study of 172,751 ParticipantsPLOS ONE, 2013
- GABA-related transcripts in the dorsolateral prefrontal cortex in mood disordersInternational Journal of Neuropsychopharmacology, 2011
- Reduced somatostatin in subgenual anterior cingulate cortex in major depressionNeurobiology of Disease, 2011
- Glial and glutamatergic markers in depression, alcoholism, and their comorbidityJournal of Affective Disorders, 2010
- Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depressionMolecular Psychiatry, 2010
- Neurocircuitry of Mood DisordersNeuropsychopharmacology, 2009
- Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Individuals With Major Depressive DisorderAmerican Journal of Psychiatry, 2009
- ToppGene Suite for gene list enrichment analysis and candidate gene prioritizationNucleic Acids Research, 2009
- Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depressionBrain Structure and Function, 2008
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005