Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

Xiao Xiao^{1

2}, Xiaolei Luo^{1

2}, Yanyun Wang³, Xinmin Pan⁴, Linbo Gao⁵, Shanling Liu^{6

7}, Lin Zhang⁸

Affiliations

¹ Department of Medical Genetics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
² Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
³ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China.
⁴ College of Basic Medicine and Forensic Medicine, Institute of Special Environmental Medicine, Forensic Judicial Appraisal Center, Henan University of Science and Technology, Luoyang, 471023, Henan, China.
⁵ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China. gaolinbo@scu.edu.cn.
⁶ Department of Medical Genetics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China. sunny630@126.com.
⁷ Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China. sunny630@126.com.
⁸ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China. zhanglin@scu.edu.cn.

PMID: 40461728
DOI: 10.1007/s12035-025-05105-y

Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

Xiao Xiao et al. Mol Neurobiol. 2025 Oct.

. 2025 Oct;62(10):12894-12906.

doi: 10.1007/s12035-025-05105-y. Epub 2025 Jun 3.

Authors

Xiao Xiao^{1

2}, Xiaolei Luo^{1

2}, Yanyun Wang³, Xinmin Pan⁴, Linbo Gao⁵, Shanling Liu^{6

7}, Lin Zhang⁸

Affiliations

¹ Department of Medical Genetics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
² Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China.
³ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China.
⁴ College of Basic Medicine and Forensic Medicine, Institute of Special Environmental Medicine, Forensic Judicial Appraisal Center, Henan University of Science and Technology, Luoyang, 471023, Henan, China.
⁵ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China. gaolinbo@scu.edu.cn.
⁶ Department of Medical Genetics, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China. sunny630@126.com.
⁷ Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 20, Section 3, Renmin Nan Road, Chengdu, 610041, Sichuan, China. sunny630@126.com.
⁸ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, No. 20, Section 3, Renmin Nan Road, Chengdu, Sichuan, 610041, People's Republic of China. zhanglin@scu.edu.cn.

PMID: 40461728
DOI: 10.1007/s12035-025-05105-y

Abstract

Lipid metabolism disruptions are implicated in nervous and mental disorders; plasma lipidomics show promise as diagnostic and therapeutic targets. However, clarification of causal relationships between plasma lipids and neuropsychiatric disorders (NPDs) remains unclear. We employed bidirectional Mendelian randomization (MR) to examine causal links between 179 plasma lipids and 17 NPDs. Significant associations in the forward MR were further investigated using linkage disequilibrium score regression (LDSC), Bayesian colocalization (COLOC) analysis, and mediation analysis. Forward MR revealed sterol ester (27:1/16:1) and diacylglycerol (16:0_18:2) elevations may increase anorexia nervosa (AN) risk, while sphingomyelin (d36:2) elevation potentially lowers it. LDSC analysis showed no substantial genetic link between the three lipids and AN, while low posterior probability of hypothesis 4 from COLOC test disputed the presence of shared variants. Besides, AN risk elevated by sterol ester's (27:1/16:1) was suggested to mediate through C-X-C chemokine 10 downregulation. In the reverse MR, we uncovered varied causal ties: ADHD increased sterol ester (27:1/20:3), phosphatidylcholines (18:0_20:3, 18:1_20:3); Alzheimer's disease lowered phosphatidylcholine (O - 18:1_20:3); Ischemic stroke tied to less phosphatidylcholine (16:0_0:0); Obsessive-compulsive disorder exhibited a dual effect, upregulating phosphatidylcholine (16:1_18:0) and downregulating sterol ester (27:1/22:6); Parkinson's disease linked to less diacylglycerol (18:1_18:3); Schizophrenia tied to more triacylglycerols (48:0,51:1); Migraine reduced sterol ester (27:1/20:2). These insights reveal causal dynamics between plasma lipids and neuropsychiatric conditions. Our findings extend the causal landscape linking the plasma lipidome to NPDs, offering insights for the discovery of novel biomarkers and therapeutic targets in these diseases.

Keywords: Causal relationships; Mendelian randomization; Neuropsychiatric disorders; Plasma lipidome; Post-MR analysis.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

References

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Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

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Interactive Effect of Plasma Lipidome on Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study

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