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Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

ABSTRACT: Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

SUBMITTER: Zhu J

PROVIDER: S-EPMC11310478 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

Zhu Jiajia J Chen Xiao X Lu Bin B Li Xue-Ying XY Wang Zi-Han ZH Cao Li-Ping LP Chen Guan-Mao GM Chen Jian-Shan JS Chen Tao T Chen Tao-Lin TL Cheng Yu-Qi YQ Chu Zhao-Song ZS Cui Shi-Xian SX Cui Xi-Long XL Deng Zhao-Yu ZY Gong Qi-Yong QY Guo Wen-Bin WB He Can-Can CC Hu Zheng-Jia-Yi ZJ Huang Qian Q Ji Xin-Lei XL Jia Feng-Nan FN Kuang Li L Li Bao-Juan BJ Li Feng F Li Hui-Xian HX Li Tao T Lian Tao T Liao Yi-Fan YF Liu Xiao-Yun XY Liu Yan-Song YS Liu Zhe-Ning ZN Long Yi-Cheng YC Lu Jian-Ping JP Qiu Jiang J Shan Xiao-Xiao XX Si Tian-Mei TM Sun Peng-Feng PF Wang Chuan-Yue CY Wang Hua-Ning HN Wang Xiang X Wang Ying Y Wang Yu-Wei YW Wu Xiao-Ping XP Wu Xin-Ran XR Wu Yan-Kun YK Xie Chun-Ming CM Xie Guang-Rong GR Xie Peng P Xu Xiu-Feng XF Xue Zhen-Peng ZP Yang Hong H Yu Hua H Yuan Min-Lan ML Yuan Yong-Gui YG Zhang Ai-Xia AX Zhao Jing-Ping JP Zhang Ke-Rang KR Zhang Wei W Zhang Zi-Jing ZJ Yan Chao-Gan CG Yu Yongqiang Y

Communications biology 20240808 1

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted t ...[more]

PMID: 39117859

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Project description:Cortical abnormalities have been noted in previous studies of major depressive disorder (MDD).To hypothesize differences in regional cortical thickness among children with MDD, children with obsessive-compulsive disorder (OCD), and healthy controls.Cross-sectional study of groups.Children's Hospital of Michigan in Detroit.A total of 24 psychotropic drug-naive pediatric patients with MDD (9 boys and 15 girls), 24 psychotropic drug-naive pediatric outpatients with OCD (8 boys and 16 girls), and 30 healthy controls (10 boys and 20 girls).Magnetic resonance imaging.Cortical thickness.In the right hemisphere of the brain, the pericalcarine gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .04), the postcentral gyrus was thinner in patients with MDD than in outpatients with OCD (P = .002) or healthy controls (P = .02), and the superior parietal gyrus was thinner in patients with MDD than in outpatients with OCD (P = .008) or healthy controls (P = .03). The outpatients with OCD and the healthy controls did not differ in these regions of the brain. The temporal pole was thicker in patients with MDD than in outpatients with OCD (P < .001) or healthy controls (P = .01), both of which groups did not differ in temporal pole thickness. The cuneus was thinner in patients with MDD than in outpatients with OCD (P = .008), but it did not differ from that in healthy controls. In the left hemisphere, the supramarginal gyrus was thinner in both patients with MDD (P = .04) and outpatients with OCD (P = .01) than in healthy controls, and the temporal pole was thicker in patients with MDD than in both healthy controls and outpatients with OCD (P < .001).To our knowledge, this is the first study to explore cortical thickness in pediatric patients with MDD. Although differences in some regions of the brain would be expected given neurobiological models of MDD, our study highlights some unexpected regions (ie, supramarginal and superior parietal gyri) that merit further investigation. These results underscore the need to expand exploration beyond the frontal-limbic circuit.

Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Dataset Information

Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

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Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

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