Human genetic risk for major depressive disorder implicates motor cortex PVALB⁺ inhibitory neurons
- 1University of Pennsylvannia
Abstract
Major depressive disorder (MDD) is highly polygenic, but the cellular and anatomical contexts through which inherited risk contributes to disease biology remain incompletely understood. Here we integrated large-scale MDD genome-wide association studies with an adult human brain single-cell discovery atlas and five independent replication atlases spanning brain regions, developmental stages, species, and disease states, comprising more than five million cells and nuclei. Across complementary polygenic mapping frameworks, MDD genetic signals were preferentially enriched in neuronal populations and consistently prioritized the primary motor cortex (M1) as a key anatomical context of risk. Subtype-level analyses highlighted PVALB inhibitory neurons and Ex-L2/4 excitatory neurons, with integrative gene prioritization nominating CNNM2 as a leading PVALB-linked MDD risk-gene candidate. CNNM2 PVALB inhibitory neurons showed elevated genetic risk scores and were enriched for synaptic, membrane-potential, and activity-related programs. In chronic-stress mouse models, Cnnm2 protein levels were reduced in M1 PV and SST inhibitory neurons, and optogenetic activation of M1 PV neurons rescued stress-induced depression-like behaviours. Anatomical tracing and activity mapping further implicated an M1-l/vlPAG circuit axis in exercise-associated antidepressant-like effects. These findings connect MDD polygenic risk to motor-cortical inhibitory-neuron biology and experimentally tractable circuit mechanisms and provide scDepBrain as a resource for exploring MDD-associated cellular programs across the brain.
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BibTeX
@misc{ma2026human,
title = {{Human genetic risk for major depressive disorder implicates motor cortex PVALB⁺ inhibitory neurons}},
author = {Y. Ma and H. Han and C. Chen and X. Huang and C. Gao and w. dai and F. Qiu and J. Li and Y. Zhou and D. Jiang and G. Zheng and Z. Zhu and C. Deng and Y. Huang and J. Zhou and C. Jops and J. England and D. Vo and X. Cai and M. Gandal and J. Su},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.26362568},
url = {https://www.medrxiv.org/content/10.64898/2026.09.08.26362568v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Human genetic risk for major depressive disorder implicates motor cortex PVALB⁺ inhibitory neurons
AU - Y. Ma
AU - H. Han
AU - C. Chen
AU - X. Huang
AU - C. Gao
AU - w. dai
AU - F. Qiu
AU - J. Li
AU - Y. Zhou
AU - D. Jiang
AU - G. Zheng
AU - Z. Zhu
AU - C. Deng
AU - Y. Huang
AU - J. Zhou
AU - C. Jops
AU - J. England
AU - D. Vo
AU - X. Cai
AU - M. Gandal
AU - J. Su
PY - 2026
DA - 2026/09/08
PB - medRxiv
DO - 10.64898/2026.09.08.26362568
UR - https://www.medrxiv.org/content/10.64898/2026.09.08.26362568v1
AB - Major depressive disorder (MDD) is highly polygenic, but the cellular and anatomical contexts through which inherited risk contributes to disease biology remain incompletely understood. Here we integrated large-scale MDD genome-wide association studies with an adult human brain single-cell discovery atlas and five independent replication atlases spanning brain regions, developmental stages, species, and disease states, comprising more than five million cells and nuclei. Across complementary polygenic mapping frameworks, MDD genetic signals were preferentially enriched in neuronal populations and consistently prioritized the primary motor cortex (M1) as a key anatomical context of risk. Subtype-level analyses highlighted PVALB inhibitory neurons and Ex-L2/4 excitatory neurons, with integrative gene prioritization nominating CNNM2 as a leading PVALB-linked MDD risk-gene candidate. CNNM2 PVALB inhibitory neurons showed elevated genetic risk scores and were enriched for synaptic, membrane-potential, and activity-related programs. In chronic-stress mouse models, Cnnm2 protein levels were reduced in M1 PV and SST inhibitory neurons, and optogenetic activation of M1 PV neurons rescued stress-induced depression-like behaviours. Anatomical tracing and activity mapping further implicated an M1-l/vlPAG circuit axis in exercise-associated antidepressant-like effects. These findings connect MDD polygenic risk to motor-cortical inhibitory-neuron biology and experimentally tractable circuit mechanisms and provide scDepBrain as a resource for exploring MDD-associated cellular programs across the brain.
ER -