Identification of specific brain cell types associated with the interplay between inflammatory bowel diseases and neuropsychiatric disorders by Cell-Stratified Mendelian Randomisation

Qi Zhou; Tian Gong; Yiling Wu; Ziwei Zhong; Haitao Deng; Chensong Sun; Xiao Lei; Junpeng Ma; Qihui Zhu; Lingyan Zhu; Chengsheng Zhang

doi:10.1016/j.ebiom.2025.105987

Identification of specific brain cell types associated with the interplay between inflammatory bowel diseases and neuropsychiatric disorders by Cell-Stratified Mendelian Randomisation

EBioMedicine. 2025 Dec:122:105987. doi: 10.1016/j.ebiom.2025.105987. Epub 2025 Nov 8.

Authors

Qi Zhou¹, Tian Gong², Yiling Wu³, Ziwei Zhong², Haitao Deng², Chensong Sun², Xiao Lei², Junpeng Ma², Qihui Zhu⁴, Lingyan Zhu⁵, Chengsheng Zhang⁶

Affiliations

¹ Department of Neurology, The First People's Hospital of Fuzhou, Fuzhou, 344000, China.
² Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China; Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China; Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China.
³ Department of Endocrinology and Metabolism, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
⁴ Stanford Health Care, 3375 Hillview Avenue, Palo Alto, CA, 94304, USA. Electronic address: Qihuizhu@stanfordhealthcare.org.
⁵ Department of Endocrinology and Metabolism, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China; Jiangxi Clinical Research Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China; Jiangxi Branch of National Clinical Research Center for Metabolic Disease, Nanchang, 330006, China. Electronic address: zly982387@126.com.
⁶ Center for Molecular Diagnosis and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China; Jiangxi Provincial Center for Advanced Diagnostic Technology and Precision Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China; Department of Medical Genetics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Dadao, Nanchang, 330209, China. Electronic address: cszhang99@ncu.edu.cn.

Abstract

Background: Inflammatory bowel disease (IBD) has been suggested to be associated with neuropsychiatric disorders, but the underlying mechanisms remain poorly understood.

Methods: We employed Cell-Stratified Mendelian Randomisation (csMR) to analyse genetic variants associated with IBD and their effects on neuropsychiatric disorders. We conducted two-sample MR analyses using the partitioned genetic variants and performed SuSiE co-localisation analysis to identify shared causal variants between GWAS traits and the single-cell eQTL data. We also examined the imaging-derived phenotypes (IDPs) to understand the structural changes in the brain.

Findings: We identified specific cell types and IDPs associated with the interplay between IBD and neuropsychiatric disorders. Importantly, the oligodendrocytes (ODC)-stratified variants associated with IBD were linked to multiple sclerosis and schizophrenia, astrocytes-stratified variants associated with ulcerative colitis (UC) were connected to obsessive-compulsive disorder and schizophrenia, and inhibitory neurons -stratified variants associated with Crohn's disease (CD) were linked to multiple sclerosis. Moreover, mediation analysis suggested that 31.4% of the association from UC to schizophrenia was mediated by alterations in mean diffusivity in the left tapetum, while structural changes in the right inferior temporal region associated with CD accounted for a 37.5% increased risk of cerebral aneurysm.

Interpretation: Our findings may facilitate understanding of the molecular mechanisms involved in diseases modulated by the gut-brain axis and develop novel therapeutic strategies for IBD and neuropsychiatric disorders.

Funding: CZ was supported by National Key Research and Development Program of China (2023YFC2705700), and operational funds from The First Affiliated Hospital of Nanchang University (500021010). LZ was supported by National Natural Science Foundation of China (82160155).

Keywords: Inflammatory bowel disease; Mendelian randomisation; Neuropsychiatric disorders; Single-cell eQTL.

MeSH terms

Brain* / metabolism
Brain* / pathology
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Inflammatory Bowel Diseases* / complications
Inflammatory Bowel Diseases* / etiology
Inflammatory Bowel Diseases* / genetics
Inflammatory Bowel Diseases* / pathology
Mendelian Randomization Analysis*
Mental Disorders* / etiology
Mental Disorders* / genetics
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci