Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis

Ruizhuo Li; Mengjuan Deng; Yuhong Lin; Wenjing Gao; Bohao Liu; Huimin Xia

doi:10.3389/fnagi.2022.938408

Genetically predicted circulating levels of glycine, glutamate, and serotonin in relation to the risks of three major neurodegenerative diseases: A Mendelian randomization analysis

Front Aging Neurosci. 2022 Sep 7:14:938408. doi: 10.3389/fnagi.2022.938408. eCollection 2022.

Authors

Ruizhuo Li^{1

2}, Mengjuan Deng³, Yuhong Lin⁴, Wenjing Gao², Bohao Liu⁵, Huimin Xia^{1

2}

Affiliations

¹ School of Medicine, South China University of Technology, Guangzhou, China.
² Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Provincial Key Laboratory of Research in Structure Birth Defect Disease, Guangzhou, China.
³ Department of Anesthesiology, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
⁴ Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁵ Xiangya School of Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.

Abstract

It has been previously postulated that blood neurotransmitters might affect risks of neurodegenerative diseases. Here, a Mendelian Randomization (MR) study was conducted to explore whether genetically predicted concentrations of glycine, glutamate and serotonin were associated with risks of Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). From three genome-wide association studies of European ancestry, single nucleotide polymorphisms strongly associated with glycine, glutamate and serotonin were selected as genetic instrumental variables. Corresponding summary statistics were also obtained from the latest genome-wide association meta-analyses of AD, PD and ALS. The inverse-variance weighted MR and multiple sensitivity analyses were performed to evaluate causal effects of genetically predicted levels of neurotransmitters on risks of neurodegenerative diseases. The statistical significance threshold was set at P < 0.0056 using the Bonferroni-correction, while 0.0056 < P < 0.05 was considered suggestive evidence for a causal association. There was a causal association of elevated blood glutamate levels with higher AD risks. The odds ratio (OR) of AD was 1.311 [95% confidence interval (CI), 1.087-1.580; P = 0.004] per one standard deviation increase in genetically predicted glutamate concentrations. There was suggestive evidence in support of a protective effect of blood serotonin on AD (OR = 0.607; 95% CI, 0.396-0.932; P = 0.022). Genetically predicted glycine levels were not associated with the risk of AD (OR = 1.145; 95% CI, 0.939-1.396; P = 0.180). Besides, MR analyses indicated no causal roles of three blood neurotransmitters in PD or ALS. In conclusion, the MR study provided evidence supporting the association of elevated blood glutamate levels with higher AD risks and the association of increased blood serotonin levels with lower AD risks. Triangulating evidence across further study designs is still warranted to elucidate the role of blood neurotransmitters in risks of neurodegenerative diseases.

Keywords: Alzheimer’s disease; Mendelian randomization; Parkinson’s disease; amyotrophic lateral sclerosis; causal inference; glutamate; glycine; serotonin.