Association Between Human Blood Metabolome and the Risk of Psychiatric Disorders.

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.

• Authors: Yiming Jia, Li Hui, Lulu Sun, Daoxia Guo, Mengyao Shi, Kaixin Zhang, Pinni Yang, Yu Wang, Fanghua Liu, Ouxi Shen, Zhengbao Zhu
• Journal: Schizophrenia bulletin (Schizophr Bull) Vol. 49 Issue 2 Pg. 428-443 (03 15 2023) ISSN: 1745-1701 [Electronic] United States
• PMID: 36124769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: [email protected].

Chemical References

• butyrylcarnitine
• 3-Hydroxybutyric Acid

Topics

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