Causal relationship between neuroticism and functional gastrointestinal disorders: a Mendelian randomized study_Chinese Journal of Evidence-Based Medicine

Authors：

HUI xin ^1,2,3 , ZHENG Ya ^2,3 , WANG Yuping ^2,3 , ZHOU Yongning ^2,3 ,  GUO Qinghong ^2,3

1. The First Clinical Medical College, Lanzhou University, Lanzhou 730000, P. R. China;
2. Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou 730000, P. R. China;
3. Gansu Province Clinical Research Center for Digestive Diseases, Lanzhou 730000, P. R. China;

Corresponding author：

GUO Qinghong, Email: gph@lzu.edu.cn

Keywords：

Neuroticism; Functional dyspepsia; Mendelian randomized analysis; Causality; Mediation analysis

DOI：

10.7507/1672-2531.202406062

Video：

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Objective To investigate the relationship between neuroticism and functional gastrointestinal disorders using Mendelian randomized (MR). Methods Based on the genome-wide association study data of neuroticism and 2 functional gastrointestinal disorders, i.e., functional dyspepsia (FD), and irritable bowel syndrome (IBS), appropriate single nucleotide polymorphisms (SNP) were extracted as instrumental variables, and inverse variance weighted (IVW) was applied as the main analysis method, and sensitivity analyses were performed by Cochran’s Q test, MR-PRESSO test, MR-Egger intercept, and leave one out analysis. Further two-step MR analyses were performed to examine the mediating effects of coffee intake, alcohol consumption, smoking, depression. Results The univariable MR analysis showed that genetically determined neuroticism was positively causally associated with the risk of developing FD and IBS (FD: OR=1.448, 95%CI 1.057 to 1.983, P=0.021; IBS: OR=1.705, 95%CI 1.210 to 2.403, P=0.002). Cochran's Q-test, MR-Egger intercept, MR-PRESSO did not observe significant heterogeneity or horizontal pleiotropy. Leave-one-out analyses also did not find a large effect of individual SNPs on the overall results. Multivariable MR analyses showed that the association between neurotic personality and elevated risk of FD and IBS prevalence persisted even after adjusting for other confounders. Further two-step MR mediation analyses revealed that depression partially mediated this effect, with mediation proportions of 59.41% (95%CI 5.69% to 113.12%) and 67.53% (95%CI 31.55% to 103.51%), respectively. Conclusion There is a degree of causal association between neuroticism and FD and IBS, and depression may play an important mediating role in this association.

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7.	Zhang YR, Deng YT, Li YZ, et al. Personality traits and brain health: a large prospective cohort study. Nat Mental Health, 2023, 1(10): 722-735.
8.	Zhang F, Baranova A, Zhou C, et al. Causal influences of neuroticism on mental health and cardiovascular disease. Hum Genet, 2021, 140(9): 1267-1281.
9.	Nakaya N, Hansen PE, Schapiro IR, et al. Personality traits and cancer survival: a Danish cohort study. Br J Cancer, 2006, 95(2): 146-152.
10.	Bunevicius A. Personality traits, patient-centered health status and prognosis of brain tumor patients. J Neurooncol, 2018, 137(3): 593-600.
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20.	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.
21.	Sanderson E, Davey Smith G, Windmeijer F, et al. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol, 2019, 48(3): 713-727.
22.	Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
23.	VanderWeele TJ. Mediation analysis: a practitioner's guide. Annu Rev Public Health, 2016, 37: 17-32.
24.	Yao S, Zhang M, Dong SS, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav, 2022, 6(11): 1569-1576.
25.	Kotov R, Gamez W, Schmidt F, et al. Linking "big" personality traits to anxiety, depressive, and substance use disorders: a meta-analysis. Psychol Bull, 2010, 136(5): 768-821.
26.	Pinto-Sanchez MI, Ford AC, Avila CA, et al. Anxiety and depression increase in a stepwise manner in parallel with multiple FGIDs and symptom severity and frequency. Am J Gastroenterol, 2015, 110(7): 1038-1048.
27.	Tegethoff M, Stalujanis E, Belardi A, et al. Chronology of onset of mental disorders and physical diseases in mental-physical comorbidity - a national representative survey of adolescents. PLoS One, 2016, 11(10): e0165196.
28.	Basso L, Boecking B, Neff P, et al. Sex differences in comorbidity combinations in the Swedish population. Biomolecules, 2022, 12(7): 949.
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30.	Muscatello MR, Bruno A, Mento C, et al. Personality traits and emotional patterns in irritable bowel syndrome. World J Gastroenterol, 2016, 22(28): 6402-6415.
31.	Ghazanfari E, Kazemnejad A, Feizi A, et al. The relationship between personality traits and psychosomatic complaints in a sample of Iranian adults. J Affect Disord, 2020, 261: 253-258.
32.	Jones SA, Van Fossen RP, Thompson WK, et al. Developmental trajectories of big five personality traits among adolescents and young adults: differences by sex, alcohol use, and marijuana use. J Pers, 2022, 90(5): 748-761.
33.	Ystrom E, Vollrath ME, Nordeng H. Effects of personality on use of medications, alcohol, and cigarettes during pregnancy. Eur J Clin Pharmacol, 2012, 68(5): 845-851.
34.	Schweren LJS, Larsson H, Vinke PC, et al. Diet quality, stress and common mental health problems: a cohort study of 121, 008 adults. Clin Nutr, 2021, 40(3): 901-906.
35.	Cryan JF, O'Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev, 2019, 99(4): 1877-2013.
36.	Clapp M, Aurora N, Herrera L, et al. Gut microbiota's effect on mental health: the gut-brain axis. Clin Pract, 2017, 7(4): 987.
37.	Zhao M, Hao Z, Li M, et al. Functional changes of default mode network and structural alterations of gray matter in patients with irritable bowel syndrome: a meta-analysis of whole-brain studies. Front Neurosci, 2023, 17: 1236069.
38.	Blankstein U, Chen J, Diamant NE, et al. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Gastroenterology, 2010, 138(5): 1783-1789.
39.	Seminowicz DA, Labus JS, Bueller JA, et al. Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology, 2010, 139(1): 48-57.
40.	Young EA, Abelson JL, Cameron OG. Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression. Biol Psychiatry, 2004, 56(2): 113-120.
41.	Leistner C, Menke A. Hypothalamic-pituitary-adrenal axis and stress. Handb Clin Neurol, 2020, 175: 55-64.
42.	Stephens MA, Mahon PB, McCaul ME, et al. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: effects of biological sex and circulating sex hormones. Psychoneuroendocrinology, 2016, 66: 47-55.
43.	Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut, 2014, 63(8): 1293-1299.
44.	Kano M, Muratsubaki T, Van Oudenhove L, et al. Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome. Sci Rep, 2017, 7(1): 12425.
45.	Fukudo S. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. J Gastroenterol, 2007, 42(Suppl 17): 48-51.
46.	Schneider KM, Blank N, Alvarez Y, et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell, 2023, 186(13): 2823-2838.
47.	Drossman DA, Tack J, Ford AC, et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a rome foundation working team report. Gastroenterology, 2018, 154(4): 1140-1171.
48.	陈启仪, 路聚保, 秦环龙, 等. “胃肠精神病学”的临床意义与干预策略. 中华胃肠外科杂志, 2022, 25(9): 771-776.

1. Black CJ, Drossman DA, Talley NJ, et al. Functional gastrointestinal disorders: advances in understanding and management. Lancet, 2020, 396(10263): 1664-1674.
2. Drossman DA, Hasler WL. Rome IV-functional GI disorders: disorders of gut-brain interaction. Gastroenterology, 2016, 150(6): 1257-1261.
3. Van Oudenhove L, Levy RL, Crowell MD, et al. Biopsychosocial aspects of functional gastrointestinal disorders: how central and environmental processes contribute to the development and expression of functional gastrointestinal disorders. Gastroenterology, 2016, 150(6): 1355-1367.
4. McAdams DP, Olson BD. Personality development: continuity and change over the life course. Annu Rev Psychol, 2010, 61: 517-542.
5. Lin J, Li L, Pan N, et al. Neural correlates of neuroticism: a coordinate-based meta-analysis of resting-state functional brain imaging studies. Neurosci Biobehav Rev, 2023, 146: 105055.
6. Mommersteeg PM, Pouwer F. Personality as a risk factor for the metabolic syndrome: a systematic review. J Psychosom Res, 2012, 73(5): 326-333.
7. Zhang YR, Deng YT, Li YZ, et al. Personality traits and brain health: a large prospective cohort study. Nat Mental Health, 2023, 1(10): 722-735.
8. Zhang F, Baranova A, Zhou C, et al. Causal influences of neuroticism on mental health and cardiovascular disease. Hum Genet, 2021, 140(9): 1267-1281.
9. Nakaya N, Hansen PE, Schapiro IR, et al. Personality traits and cancer survival: a Danish cohort study. Br J Cancer, 2006, 95(2): 146-152.
10. Bunevicius A. Personality traits, patient-centered health status and prognosis of brain tumor patients. J Neurooncol, 2018, 137(3): 593-600.
11. Sanderson E, Glymour MM, Holmes MV, et al. Mendelian randomization. Nat Rev Methods Primers, 2022, 2: 6.
12. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ, 2018, 362: k601.
13. Bowden J, Holmes MV. Meta-analysis and Mendelian randomization: a review. Res Synth Methods, 2019, 10(4): 486-496.
14. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
15. Palmer TM, Lawlor DA, Harbord RM, et al. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res, 2012, 21(3): 223-242.
16. Burgess S, Thompson SG. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
17. Burgess S, Davies NM, Thompson SG. Bias due to participant overlap in two-sample Mendelian randomization. Genet Epidemiol, 2016, 40(7): 597-608.
18. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
19. Yavorska OO, Burgess S. MendelianRandomization: an R package for performing Mendelian randomization analyses using summarized data. Int J Epidemiol, 2017, 46(6): 1734-1739.
20. 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.
21. Sanderson E, Davey Smith G, Windmeijer F, et al. An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings. Int J Epidemiol, 2019, 48(3): 713-727.
22. Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
23. VanderWeele TJ. Mediation analysis: a practitioner's guide. Annu Rev Public Health, 2016, 37: 17-32.
24. Yao S, Zhang M, Dong SS, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav, 2022, 6(11): 1569-1576.
25. Kotov R, Gamez W, Schmidt F, et al. Linking "big" personality traits to anxiety, depressive, and substance use disorders: a meta-analysis. Psychol Bull, 2010, 136(5): 768-821.
26. Pinto-Sanchez MI, Ford AC, Avila CA, et al. Anxiety and depression increase in a stepwise manner in parallel with multiple FGIDs and symptom severity and frequency. Am J Gastroenterol, 2015, 110(7): 1038-1048.
27. Tegethoff M, Stalujanis E, Belardi A, et al. Chronology of onset of mental disorders and physical diseases in mental-physical comorbidity - a national representative survey of adolescents. PLoS One, 2016, 11(10): e0165196.
28. Basso L, Boecking B, Neff P, et al. Sex differences in comorbidity combinations in the Swedish population. Biomolecules, 2022, 12(7): 949.
29. Jones MP, Oudenhove LV, Koloski N, et al. Early life factors initiate a 'vicious circle' of affective and gastrointestinal symptoms: a longitudinal study. United European Gastroenterol J, 2013, 1(5): 394-402.
30. Muscatello MR, Bruno A, Mento C, et al. Personality traits and emotional patterns in irritable bowel syndrome. World J Gastroenterol, 2016, 22(28): 6402-6415.
31. Ghazanfari E, Kazemnejad A, Feizi A, et al. The relationship between personality traits and psychosomatic complaints in a sample of Iranian adults. J Affect Disord, 2020, 261: 253-258.
32. Jones SA, Van Fossen RP, Thompson WK, et al. Developmental trajectories of big five personality traits among adolescents and young adults: differences by sex, alcohol use, and marijuana use. J Pers, 2022, 90(5): 748-761.
33. Ystrom E, Vollrath ME, Nordeng H. Effects of personality on use of medications, alcohol, and cigarettes during pregnancy. Eur J Clin Pharmacol, 2012, 68(5): 845-851.
34. Schweren LJS, Larsson H, Vinke PC, et al. Diet quality, stress and common mental health problems: a cohort study of 121, 008 adults. Clin Nutr, 2021, 40(3): 901-906.
35. Cryan JF, O'Riordan KJ, Cowan CSM, et al. The microbiota-gut-brain axis. Physiol Rev, 2019, 99(4): 1877-2013.
36. Clapp M, Aurora N, Herrera L, et al. Gut microbiota's effect on mental health: the gut-brain axis. Clin Pract, 2017, 7(4): 987.
37. Zhao M, Hao Z, Li M, et al. Functional changes of default mode network and structural alterations of gray matter in patients with irritable bowel syndrome: a meta-analysis of whole-brain studies. Front Neurosci, 2023, 17: 1236069.
38. Blankstein U, Chen J, Diamant NE, et al. Altered brain structure in irritable bowel syndrome: potential contributions of pre-existing and disease-driven factors. Gastroenterology, 2010, 138(5): 1783-1789.
39. Seminowicz DA, Labus JS, Bueller JA, et al. Regional gray matter density changes in brains of patients with irritable bowel syndrome. Gastroenterology, 2010, 139(1): 48-57.
40. Young EA, Abelson JL, Cameron OG. Effect of comorbid anxiety disorders on the hypothalamic-pituitary-adrenal axis response to a social stressor in major depression. Biol Psychiatry, 2004, 56(2): 113-120.
41. Leistner C, Menke A. Hypothalamic-pituitary-adrenal axis and stress. Handb Clin Neurol, 2020, 175: 55-64.
42. Stephens MA, Mahon PB, McCaul ME, et al. Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: effects of biological sex and circulating sex hormones. Psychoneuroendocrinology, 2016, 66: 47-55.
43. Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut, 2014, 63(8): 1293-1299.
44. Kano M, Muratsubaki T, Van Oudenhove L, et al. Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome. Sci Rep, 2017, 7(1): 12425.
45. Fukudo S. Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. J Gastroenterol, 2007, 42(Suppl 17): 48-51.
46. Schneider KM, Blank N, Alvarez Y, et al. The enteric nervous system relays psychological stress to intestinal inflammation. Cell, 2023, 186(13): 2823-2838.
47. Drossman DA, Tack J, Ford AC, et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): a rome foundation working team report. Gastroenterology, 2018, 154(4): 1140-1171.
48. 陈启仪, 路聚保, 秦环龙, 等. “胃肠精神病学”的临床意义与干预策略. 中华胃肠外科杂志, 2022, 25(9): 771-776.

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