Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders

Yiming Jia; Li Hui; Lulu Sun; Daoxia Guo; Mengyao Shi; Kaixin Zhang; Pinni Yang; Yu Wang; Fanghua Liu; Ouxi Shen; Zhengbao Zhu

doi:10.1093/schbul/sbac130

Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders

Schizophr Bull. 2023 Mar 15;49(2):428-443. doi: 10.1093/schbul/sbac130.

Authors

Yiming Jia¹, Li Hui², Lulu Sun¹, Daoxia Guo^{1

3}, Mengyao Shi¹, Kaixin Zhang¹, Pinni Yang¹, Yu Wang¹, Fanghua Liu¹, Ouxi Shen⁴, Zhengbao Zhu¹

Affiliations

¹ Department of Epidemiology, School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, China.
² Research Center of Biological Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou, China.
³ School of Nursing, Medical College of Soochow University, Suzhou, China.
⁴ Department of Occupational Health, Suzhou Industrial Park Center for Disease Control and Prevention, Suzhou, China.

Abstract

Background and hypothesis: To identify promising drug targets for psychiatric disorders, we applied Mendelian randomization (MR) design to systematically screen blood metabolome for potential mediators of psychiatric disorders and further predict target-mediated side effects.

Study design: We selected 92 unique blood metabolites from 3 metabolome genome-wide association studies (GWASs) with totally 147 827 participants. Summary statistics for bipolar disorder (BIP), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), schizophrenia (SCZ), panic disorder (PD), autistic spectrum disorder (ASD), and anorexia nervosa (AN) originated from the Psychiatric Genomics Consortium, involving 1 143 340 participants. Mendelian randomization (MR) analyses were conducted to estimate associations of blood metabolites with psychiatric disorders. Phenome-wide MR analysis was further performed to predict side effects mediated by metabolite-targeted interventions.

Results: Eight metabolites were identified associated with psychiatric disorders, including five established mediators: N-acetylornithine (BIP: OR, 0.72 [95% CI, 0.66-0.79]; SCZ: OR, 0.74 [0.64-0.84]), glycine (BIP: OR, 0.62 [0.50-0.77]), docosahexaenoic acid (MDD: OR, 0.96 [0.94-0.97]), 3-Hydroxybutyrate (MDD: OR, 1.14 [1.08-1.21]), butyrylcarnitine (SCZ: OR, 1.22 [1.12-1.32]); and three novel mediators: 1-arachidonoylglycerophosphocholine (1-arachidonoyl-GPC)(BIP: OR, 0.31 [0.23-0.41]), glycoproteins (BIP: OR, 0.94 [0.92-0.97]), sphingomyelins (AN: OR, 1.12 [1.06-1.19]). Phenome-wide MR analysis showed that all identified metabolites except for N-acetylornithine and 3-Hydroxybutyrate had additional effects on nonpsychiatric diseases, while glycine, 3-Hydroxybutyrate, N-acetylornithine, and butyrylcarnitine had no adverse side effects.

Conclusions: This MR study identified five established and three novel mediators for psychiatric disorders. N-acetylornithine, glycine, 3-Hydroxybutyrate, and butyrylcarnitine might be promising targets against psychiatric disorders with no predicted adverse side effects.

Keywords: Mendelian randomization; antipsychotics; biomarkers; metabolites; psychiatric disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Hydroxybutyric Acid
Attention Deficit Disorder with Hyperactivity*
Depressive Disorder, Major*
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis

Substances

butyrylcarnitine
3-Hydroxybutyric Acid