Convergent molecular, cellular, and neural signatures of major depressive disorder
Authors: Anderson Kevin M , Collins Meghan A , Kong Ru , Fang Kacey , Li Jingwei , He Tong , Chekroud Adam M , Yeo B.T. Thomas , Holmes Avram J 
Published: February 2020

AbstractMajor depressive disorder emerges from the complex interactions of biological systems that span across genes and molecules through cells, circuits, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to the onset and maintenance of depression requires a multi-scale approach, encompassing measures of brain structure and function as well as genetic and cell-specific genomic data. Here, we examined anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Genome Superstruct Project, and ENIGMA (combined N≥23,723). Integrative analyses incorporated measures of cortical gene expression, post-mortem patient transcriptional data, depression GWAS, and single-cell transcription. Neuroimaging correlates of depression and negative affect were consistent across the three independent datasets. Linkingex-vivogene downregulation within-vivoneuroimaging, we found that genomic correlates of depression-linked neuroimaging phenotypes tracked gene downregulation in post-mortem cortical tissue samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data implicated somatostatin interneurons and astrocytes as consistent cell associates of depression, through bothin-vivoimaging andex-vivocortical 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 multi-scale approaches, the genomic correlates of depression-linked brain function and structure were enriched for known and novel disorder relevant molecular pathways. These findings bridge across levels to connect specific genes, cell classes, and biological pathways toin-vivoimaging correlates of depression.Key FindingsMajor depressive disorder and negative affect are associated with replicable profiles of cortical anatomy and function across independent population-level neuroimaging datasets (combined N≥23,723).Somatostatin interneurons are consistent spatial transcriptional associates ofin-vivodepression-linked imaging phenotypes.Integrative single-cell gene expression analysis associate somatostatin interneurons and astrocytes with bothin-vivodepression-linked imaging andex-vivogene downregulation in independent MDD cortical tissue samples.Transcriptional correlates ofin-vivodepression imaging phenotypes selectively capture gene downregulation in post-mortem tissue samples from patients with depression, but not other psychiatric disorders.Indicating that some cell classes are preferentially sensitive to inherited disease liability, genome-wide risk for depression is enriched among interneurons, but not glia.Gene associates of depression-linked anatomy and function identify specific neurotransmitter systems, molecular signaling pathways, and receptors, suggesting possible targets for pharmaceutical intervention.