Causal relationship between cerebrospinal fluid metabolites and tic disorders: a two-sample Mendelian randomization study_West China Medical Journal

Authors：

LI Zehao ¹ ,  WANG Hai ² , LI Yan ²

1. First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P. R. China;
2. First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P. R. China;

Corresponding author：

WANG Hai, Email: wanghai@hljucm.net

Keywords：

Tic disorders; cerebrospinal fluid metabolites; two-sample Mendelian randomization; causal relationship

DOI：

10.7507/1002-0179.202408054

Video：

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Objective To analyze the causal relationship between cerebrospinal fluid (CSF) metabolites and tic disorder (TD) based on two-sample Mendelian randomization (MR). Methods CSF metabolites data from humans were downloaded from genome-wide association study databases, and CSF metabolites were selected as exposure factors. single nucleotide polymorphisms (SNPs) strongly associated with the exposure factors and independent of each other were selected as instrumental variables. The TD dataset from the Finngen database was downloaded, including 365 cases of TD and 411 816 controls. Analysis was conducted using inverse variance weighting, MR-Egger, weighted median, weighted mode, and simple mode. Sensitivity analysis was conducted using leave-one-out, and multiple-effects testing was conducted using MR-Egger and MR-PRESSO. Heterogeneity was detected using Cochran’s Q. Results A total of 9 CSF metabolites were found to have a causal relationship with the occurrence and development of TD (P<0.05), with a total of 394 SNPs included in the analysis. Inverse variance weighting results showed that N-acetylneuraminic acid [odds ratio (OR)=2.715, 95% confidence interval (CI) (1.102, 6.961), P=0.030], γ-glutamylglutamine [OR=1.402, 95%CI (1.053, 1.868), P=0.021], lysine [OR=2.816, 95%CI (1.084, 7.319), P=0.034] could increase the risk of TD. Cysteinylglycine disulfide [OR=0.437, 95%CI (0.216, 0.885), P=0.021], propionylcarnitine [OR=0.762, 95%CI (0.616, 0.941), P=0.012], pantothenate [OR=0.706, 95%CI (0.523, 0.952), P=0.023], gulareic acid [OR=0.758, 95%CI (0.579, 0.992), P=0.044], and cysteine-glycine [OR=0.799, 95%CI (0.684, 0.934), P=0.005] could reduce the risk of TD. The results of leave-one-out sensitivity analysis were stable, and no horizontal pleiotropy or heterogeneity was observed. Conclusions N-acetylneuraminic acid, γ-glutamylglutamine, and lysine can increase the risk of TD, but cysteinylglycine disulfide, propionylcarnitine, pantothenate, gulagic acid and cysteine-glycine can reduce the risk of TD. However, the mechanism of their effects on TD still needs to be further explored.

1.	王帅, 戎萍. 儿童抽动障碍复发相关因素及治疗的研究进展. 中华中医药杂志, 2023, 38(8): 3747-3751.
2.	美国精神学会. 精神障碍诊断与统计手册. 张道龙, 等, 译. 5 版. 北京: 北京大学出版社, 2014: 34-35.
3.	卢青, 孙丹, 刘智胜. 中国抽动障碍诊断和治疗专家共识解读. 中华实用儿科临床杂志, 2021, 36(9): 647-653.
4.	姜妍琳, 张蔷, 翟睿, 等. 中国儿童抽动障碍患病率及危险因素系统评价. 中国儿童保健杂志, 2023, 31(6): 661-667.
5.	王诗妍, 马丙祥, 李瑞星, 等. 儿童抽动障碍研究进展. 中国中西医结合儿科学, 2021, 13(4): 297-301.
6.	Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group Ⅱ mGluR. J Neurochem, 2004, 89(4): 876-885.
7.	Widomska J, De Witte W, Buitelaar JK, et al. Molecular landscape of Tourette’s disorder. Int J Mol Sci, 2023, 24(2): 1428.
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9.	Panyard DJ, Kim KM, Darst BF, et al. Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations. Commun Biol, 2021, 4(1): 63.
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11.	Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
12.	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
13.	Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
14.	Bowden J, Del Greco MF, Minelli C, et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med, 2017, 36(11): 1783-1802.
15.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
16.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
17.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
18.	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
19.	Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci, 2012, 1253(1): 16-36.
20.	Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol, 2014, 14(10): 653-666.
21.	Varki A. Colloquium paper: uniquely human evolution of sialic acid genetics and biology. Proc Natl Acad Sci U S A, 2010, 107(Suppl 2): 8939-8946.
22.	侯晓君, 林珊, 林祥泉, 等. 抽动障碍儿童 Th 淋巴细胞及其亚群的变化. 中国当代儿科杂志, 2018, 20(7): 519-523.
23.	Tate SS, Meister A. Gamma-glutamyl transpeptidase: catalytic, structural and functional aspects. Mol Cell Biochem, 1981, 39: 357-368.
24.	Liu Y, Hyde AS, Simpson MA, et al. Emerging regulatory paradigms in glutathione metabolism. Adv Cancer Res, 2014, 122: 69-101.
25.	Do KQ, Lauer CJ, Schreiber W, et al. Gamma-glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem, 1995, 65(6): 2652-2662.
26.	Hammond JW, Potter M, Truscott R, et al. Gamma-glutamylglutamine identified in plasma and cerebrospinal fluid from hyperammonaemic patients. Clin Chim Acta, 1990, 194(2/3): 173-183.
27.	Hao J, Zhang X, Liu Y, et al. Cross-sectional exploration of the relationship between glutamate abnormalities and tic disorder severity using proton magnetic resonance spectroscopy. Phenomics, 2022, 3(2): 138-147.
28.	Chang FM. Update current understanding of neurometabolic disorders related to lysine metabolism. Epilepsy Behav, 2023, 146: 109363.
29.	Wang Z, Liu H. Lysine methylation regulates nervous system diseases. Neuropeptides, 2019, 76: 101929.
30.	García-Giménez JL, Romá-Mateo C, Pérez-Machado G, et al. Role of glutathione in the regulation of epigenetic mechanisms in disease. Free Radic Biol Med, 2017, 112: 36-48.
31.	Müller T, Muhlack S. Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson’s disease patients. Mov Disord, 2011, 26(3): 543-546.
32.	Loffredo L, Spalice A, Salvatori F, et al. Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. BMC Pediatr, 2020, 20(1): 127.
33.	Stein AF, Dills RL, Klaassen CD. High-performance liquid chromatographic analysis of glutathione and its thiol and disulfide degradation products. J Chromatogr, 1986, 381(2): 259-270.
34.	Dambrova M, Makrecka-Kuka M, Kuka J, et al. Acylcarnitines: nomenclature, biomarkers, therapeutic potential, drug targets, and clinical trials. Pharmacol Rev, 2022, 74(3): 506-551.
35.	Kazanasmaz Halil, Karaca M. Investigation of alanine, propionylcarnitine (C3) and 3-hydroxyisovalerylcarnitine (C5-OH) levels in patients with partial biotinidase deficiency. Turk J Biochem, 2019, 44(4): 482-486.
36.	Gordon S, Lee JS, Scott TM, et al. Metabolites and MRI-derived markers of AD/ADRD risk in a puerto rican cohort. Res Sq, 2024: rs. 3. rs-3941791.
37.	Swell L, Boiter TA, Field H Jr, et al. Pantothenate and dietary cholesterol in the maintenance of blood and tissue cholesterol esters. J Nutr, 1955, 57(1): 121-132.
38.	Hayflick SJ. Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans, 2014, 42(4): 1063-1068.
39.	Kurup RK, Kurup PA. Hypothalamic digoxin deficiency in obsessive compulsive disorder and la Tourette’s syndrome. Int J Neurosci, 2002, 112(7): 797-816.

1. 王帅, 戎萍. 儿童抽动障碍复发相关因素及治疗的研究进展. 中华中医药杂志, 2023, 38(8): 3747-3751.
2. 美国精神学会. 精神障碍诊断与统计手册. 张道龙, 等, 译. 5 版. 北京: 北京大学出版社, 2014: 34-35.
3. 卢青, 孙丹, 刘智胜. 中国抽动障碍诊断和治疗专家共识解读. 中华实用儿科临床杂志, 2021, 36(9): 647-653.
4. 姜妍琳, 张蔷, 翟睿, 等. 中国儿童抽动障碍患病率及危险因素系统评价. 中国儿童保健杂志, 2023, 31(6): 661-667.
5. 王诗妍, 马丙祥, 李瑞星, 等. 儿童抽动障碍研究进展. 中国中西医结合儿科学, 2021, 13(4): 297-301.
6. Olszewski RT, Bukhari N, Zhou J, et al. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group Ⅱ mGluR. J Neurochem, 2004, 89(4): 876-885.
7. Widomska J, De Witte W, Buitelaar JK, et al. Molecular landscape of Tourette’s disorder. Int J Mol Sci, 2023, 24(2): 1428.
8. Leckman JF, Riddle MA, Berrettini WH, et al. Elevated CSF dynorphin A [1-8] in Tourette’s syndrome. Life Sci, 1988, 43(24): 2015-2023.
9. Panyard DJ, Kim KM, Darst BF, et al. Cerebrospinal fluid metabolomics identifies 19 brain-related phenotype associations. Commun Biol, 2021, 4(1): 63.
10. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
11. Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
12. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol, 2013, 37(7): 658-665.
13. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol, 2011, 40(3): 740-752.
14. Bowden J, Del Greco MF, Minelli C, et al. A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization. Stat Med, 2017, 36(11): 1783-1802.
15. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
16. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
17. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
18. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
19. Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci, 2012, 1253(1): 16-36.
20. Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol, 2014, 14(10): 653-666.
21. Varki A. Colloquium paper: uniquely human evolution of sialic acid genetics and biology. Proc Natl Acad Sci U S A, 2010, 107(Suppl 2): 8939-8946.
22. 侯晓君, 林珊, 林祥泉, 等. 抽动障碍儿童 Th 淋巴细胞及其亚群的变化. 中国当代儿科杂志, 2018, 20(7): 519-523.
23. Tate SS, Meister A. Gamma-glutamyl transpeptidase: catalytic, structural and functional aspects. Mol Cell Biochem, 1981, 39: 357-368.
24. Liu Y, Hyde AS, Simpson MA, et al. Emerging regulatory paradigms in glutathione metabolism. Adv Cancer Res, 2014, 122: 69-101.
25. Do KQ, Lauer CJ, Schreiber W, et al. Gamma-glutamylglutamine and taurine concentrations are decreased in the cerebrospinal fluid of drug-naive patients with schizophrenic disorders. J Neurochem, 1995, 65(6): 2652-2662.
26. Hammond JW, Potter M, Truscott R, et al. Gamma-glutamylglutamine identified in plasma and cerebrospinal fluid from hyperammonaemic patients. Clin Chim Acta, 1990, 194(2/3): 173-183.
27. Hao J, Zhang X, Liu Y, et al. Cross-sectional exploration of the relationship between glutamate abnormalities and tic disorder severity using proton magnetic resonance spectroscopy. Phenomics, 2022, 3(2): 138-147.
28. Chang FM. Update current understanding of neurometabolic disorders related to lysine metabolism. Epilepsy Behav, 2023, 146: 109363.
29. Wang Z, Liu H. Lysine methylation regulates nervous system diseases. Neuropeptides, 2019, 76: 101929.
30. García-Giménez JL, Romá-Mateo C, Pérez-Machado G, et al. Role of glutathione in the regulation of epigenetic mechanisms in disease. Free Radic Biol Med, 2017, 112: 36-48.
31. Müller T, Muhlack S. Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson’s disease patients. Mov Disord, 2011, 26(3): 543-546.
32. Loffredo L, Spalice A, Salvatori F, et al. Oxidative stress and gut-derived lipopolysaccharides in children affected by paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. BMC Pediatr, 2020, 20(1): 127.
33. Stein AF, Dills RL, Klaassen CD. High-performance liquid chromatographic analysis of glutathione and its thiol and disulfide degradation products. J Chromatogr, 1986, 381(2): 259-270.
34. Dambrova M, Makrecka-Kuka M, Kuka J, et al. Acylcarnitines: nomenclature, biomarkers, therapeutic potential, drug targets, and clinical trials. Pharmacol Rev, 2022, 74(3): 506-551.
35. Kazanasmaz Halil, Karaca M. Investigation of alanine, propionylcarnitine (C3) and 3-hydroxyisovalerylcarnitine (C5-OH) levels in patients with partial biotinidase deficiency. Turk J Biochem, 2019, 44(4): 482-486.
36. Gordon S, Lee JS, Scott TM, et al. Metabolites and MRI-derived markers of AD/ADRD risk in a puerto rican cohort. Res Sq, 2024: rs. 3. rs-3941791.
37. Swell L, Boiter TA, Field H Jr, et al. Pantothenate and dietary cholesterol in the maintenance of blood and tissue cholesterol esters. J Nutr, 1955, 57(1): 121-132.
38. Hayflick SJ. Defective pantothenate metabolism and neurodegeneration. Biochem Soc Trans, 2014, 42(4): 1063-1068.
39. Kurup RK, Kurup PA. Hypothalamic digoxin deficiency in obsessive compulsive disorder and la Tourette’s syndrome. Int J Neurosci, 2002, 112(7): 797-816.

West China Medical Journal

Latest ArticlesCausal relationship between cerebrospinal fluid metabolites and tic disorders: a two-sample Mendelian randomization study

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