The causal relationship between depression and chronic pancreatitis: A Mendelian randomization study

Abstract

Observational studies have suggested a high prevalence of depression among patients with chronic pancreatitis (CP). However, the effects of depression on CP and the causal relationship between the two conditions remain unclear. We performed two-sample and multivariable Mendelian randomization (MR) analyses, as well as a two-step MR analysis, to investigate their causal associations. Data on depression and CP were obtained from summary statistics of non-overlapping samples in a genome-wide association study. Two-sample and multivariable MR analyses were conducted to explore the association between depression and CP. A subsequent two-step MR analysis explored the causal pathways between the two conditions and the role of mediators in this process. Genetically, predicted depression (per 1 standard deviation) showed a positive association with CP (odds ratio [OR]: 1.39; 95% confidence interval [CI]: 1.03 - 1.86; P = 0.03). The causal relationship was confirmed after adjusting for smoking, drinking, type 2 diabetes, body mass index, and triglycerides. We found that triglycerides (OR: 1.02; 95% CI: 1.01 - 1.04; P = 0.004), type 2 diabetes (OR: 1.03; 95% CI: 1.01 - 1.06; P = 0.030), and smoking initiation (OR: 1.06; 95% CI: 1.01 - 1.13; P = 0.046) may mediate the causal relationship between depression and CP, with the mediating effect accounting for 6.14%, 7.84%, and 17.06% of the total effect, respectively. Our study provides evidence for an independent causal effect of depression on CP, offering new insights into the correlation between depression and inflammation. Further research is necessary to clarify the pathophysiological mechanisms underlying this causal association.

Keywords

Depression / Chronic pancreatitis / Mendelian randomization / Genome-wide association study

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81972655), the Shanghai Industry-university Research Practice Project (2023; Grant No. 81972655), and the Shanghai Jiao Tong University “Jiaotong Star” Plan Medical Engineering Cross Research Project (Grant No. 20230103 and YG2021QN07).

Conflict of interest

The authors declare no competing interests.

References

[1] Whitcomb DC, Frulloni L, Garg P, et al. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016; 16(2):218-224. doi: 10.1016/j.pan.2016.02.001

[2] Stram M, Liu S, Singhi AD. Chronic pancreatitis. Surg Pathol Clin. 2016; 9(4):643-659. doi: 10.1016/j.path.2016.05.008

[3] Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet (London, England). 2020; 396(10249):499-512. doi: 10.1016/S0140-6736(20)31318-0

[4] Singh VK, Yadav D, Garg PK. Diagnosis and management of chronic pancreatitis: A review. JAMA. 2019; 322(24): 2422-2434. doi: 10.1001/jama.2019.19411

[5] Vege SS, Chari ST. Chronic pancreatitis. N Engl J Med. 2022; 386(9):869-878. doi: 10.1056/NEJMcp1809396

[6] Zou WB, Ru N, Wu H, et al. Guidelines for the diagnosis and treatment of chronic pancreatitis in China (2018 edition). Hepatobiliary Pancreat Dis Int. 2019; 18(2):103-109. doi: 10.1016/j.hbpd.2019.02.004

[7] Phillips AE, Faghih M, Drewes AM, et al. Psychiatric comorbidity in patients with chronic pancreatitis associates with pain and reduced quality of life. Am J Gastroenterol. 2020; 115(12):2077-2085. doi: 10.14309/ajg.0000000000000782

[8] Yadav D, Timmons L, Benson JT, Dierkhising RA, Chari ST. Incidence, prevalence, and survival of chronic pancreatitis: A population-based study. Am J Gastroenterol. 2011; 106(12):2192-2199. doi: 10.1038/ajg.2011.328

[9] Gore FM, Bloem PJ, Patton GC, et al. Global burden of disease in young people aged 10-24 years: A systematic analysis. Lancet. 2011; 377(9783):2093-2102. doi: 10.1016/S0140-6736(11)60512-6

[10] McCarron RM, Shapiro B, Rawles J, Luo J. Depression. Ann Intern Med. 2021; 174(5):ITC65-ITC80. doi: 10.7326/AITC202105180

[11] Malhi GS, Mann JJ. Depression. Lancet. 2018; 392(10161):2299-2312. doi: 10.1016/S0140-6736(18)31948-2

[12] Beurel E, Toups M, Nemeroff CB. The bidirectional relationship of depression and inflammation: Double trouble. Neuron. 2020; 107(2):234-256. doi: 10.1016/j.neuron.2020.06.002

[13] Kohler CA, Freitas TH, Stubbs B, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: Systematic review and meta-analysis. Mol Neurobiol. 2018; 55(5):4195-4206. doi: 10.1007/s12035-017-0632-1

[14] Hasler G, Pine DS, Gamma A, et al. The associations between psychopathology and being overweight: A 20-year prospective study. Psychol Med. 2004; 34(6):1047-1057. doi: 10.1017/s0033291703001697

[15] Burgess S, Davey Smith G, Davies NM, et al. Guidelines for performing Mendelian randomization investigations: update for summer 2023. Wellcome Open Res. 2019;4:186. doi: 10.12688/wellcomeopenres.15555.3

[16] Burgess S, Small DS, Thompson SG. A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res. 2017; 26(5):2333-2355. doi: 10.1177/0962280215597579

[17] Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008; 27(8):1133-1163. doi: 10.1002/sim.3034

[18] Howard DM, Adams MJ, Clarke TK, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019; 22(3):343-352. doi: 10.1038/s41593-018-0326-7

[19] Mao X, Mao S, Sun H, et al. Causal associations between modifiable risk factors and pancreatitis: A comprehensive Mendelian randomization study. Front Immunol. 2023;14:1091780. doi: 10.3389/fimmu.2023.1091780

[20] Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375:n2233. doi: 10.1136/bmj.n2233

[21] Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomization: The STROBE-MR statement. JAMA. 2021; 326(16):1614-1621. doi: 10.1001/jama.2021.18236

[22] Wray NR, Ripke S, Mattheisen M, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018; 50(5):668-681. doi: 10.1038/s41588-018-0090-3

[23] Howard DM, Adams MJ, Shirali M, et al. Genome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways. Nat Commun. 2018; 9(1):1470. doi: 10.1038/s41467-018-03819-3

[24] Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023; 613(7944):508-518. doi: 10.1038/s41586-022-05473-8

[25] Hart PA, Conwell DL. Chronic pancreatitis: Managing a difficult disease. Am J Gastroenterol. 2020; 115(1):49-55. doi: 10.14309/ajg.0000000000000421

[26] 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. doi: 10.1177/0962280210394459

[27] Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. doi: 10.1007/s10654-017-0255-x

[28] 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. doi: 10.1093/ije/dyv080

[29] Brion MJ, Shakhbazov K, Visscher PM. Calculating statistical power in Mendelian randomization studies. Int J Epidemiol. 2013; 42(5):1497-14501. doi: 10.1093/ije/dyt179

[30] Burgess S, Thompson SG. Multivariable Mendelian randomization: The use of pleiotropic genetic variants to estimate causal effects. Am J Epidemiol. 2015; 181(4):251-260. doi: 10.1093/aje/kwu283

[31] Rees JMB, Wood AM, Burgess S. Extending the MR-Egger method for multivariable Mendelian randomization to correct for both measured and unmeasured pleiotropy. Stat Med. 2017; 36(29):4705-4718. doi: 10.1002/sim.7492

[32] Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018; 50(5):693-698. doi: 10.1038/s41588-018-0099-7

[33] 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. doi: 10.1007/s10654-021-00757-1

[34] Richardson TG, Sanderson E, Palmer TM, et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med. 2020; 17(3):e1003062. doi: 10.1371/journal.pmed.1003062

[35] Liu M, Jiang Y, Wedow R, et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat Genet. 2019; 51(2):237-244. doi: 10.1038/s41588-018-0307-5

[36] Xue A, Wu Y, Zhu Z, et al. Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes. Nat Commun. 2018; 9(1):2941. doi: 10.1038/s41467-018-04951-w

[37] Yuan S, Giovannucci EL, Larsson SC. Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study. NPJ Genom Med. 2021; 6(1):27. doi: 10.1038/s41525-021-00189-6

[38] Rich KL, Abu-El-Haija M, Nathan JD, Lynch-Jordan A. The role of psychology in the care of children with pancreatitis. Pancreas. 2020; 49(7):887-890. doi: 10.1097/MPA.0000000000001598

[39] Makar M, Vodusek Z, Xia W, Greenberg P, Abdelsayed GG. Rising prevalence of anxiety and depression in chronic pancreatitis: A nationwide analysis. Pancreas. 2022; 51(4):325-329. doi: 10.1097/MPA.0000000000002019

[40] Chen C, Zhou Y, Wang D, et al. Anxiety, depression, and coping styles among patients with chronic pancreatitis in East China. BMC Psychiatry. 2023; 23(1):212. doi: 10.1186/s12888-023-04691-2

[41] Dunbar E, Greer PJ, Melhem N, et al. Constant-severe pain in chronic pancreatitis is associated with genetic loci for major depression in the NAPS2 cohort. J Gastroenterol. 2020; 55(10):1000-1009. doi: 10.1007/s00535-020-01703-w

[42] Yadav D, Askew RL, Palermo T, et al. Association of chronic pancreatitis pain features with physical, mental, and social health. Clin Gastroenterol Hepatol. 2023; 21(7):1781-1791.e4. doi: 10.1016/j.cgh.2022.09.026

[43] Sarkar S, Sarkar P, Revanth M, et al. Pain, depression, and poor quality of life in chronic pancreatitis: Relationship with altered brain metabolites. Pancreatology. 2022; 22(6): 688-697. doi: 10.1016/j.pan.2022.06.007

[44] Singh VV, Toskes PP. Medical therapy for chronic pancreatitis pain. Curr Gastroenterol Rep. 2003; 5(2):110-116. doi: 10.1007/s11894-003-0079-6

[45] Shah R, Haydek C, Mulki R, Qayed E. Incidence and predictors of 30-day readmissions in patients hospitalized with chronic pancreatitis: A nationwide analysis. Pancreatology. 2018; 18(4):386-393. doi: 10.1016/j.pan.2018.04.006

[46] Ruan X, Chen J, Sun Y, et al. Depression and 24 gastrointestinal diseases: A Mendelian randomization study. Transl Psychiatry. 2023; 13(1):146. doi: 10.1038/s41398-023-02459-6

[47] Komatsu H. Novel therapeutic GPCRs for psychiatric disorders. Int J Mol Sci. 2015; 16(6):14109-14121. doi: 10.3390/ijms160614109

[48] Nista EC, De Lucia SS, Manilla V, et al. Autoimmune pancreatitis: From pathogenesis to treatment. Int J Mol Sci. 2022; 23(20):12667. doi: 10.3390/ijms232012667

[49] Cieslak MC, Castelfranco AM, Roncalli V, Lenz PH, Hartline DK. t-Distributed Stochastic neighbor embedding (t-SNE): A tool for eco-physiological transcriptomic analysis. Genomics. 2020;51:100723. doi: 10.1016/j.margen.2019.100723

[50] Kwon H, Ali ZA, Wong BM. Harnessing semi-supervised machine learning to automatically predict bioactivities of per- and polyfluoroalkyl substances (PFASs). Environ Sci Technol Lett. 2023; 10(11):1017-1022. doi: 10.1021/acs.estlett.2c00530

[51] Nemeroff CB. New vistas in neuropeptide research in neuropsychiatry: Focus on corticotropin-releasing factor. Neuropsychopharmacology. 1992; 6(2):69-75.

[52] Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol. 1991; 38(5):537-559. doi: 10.1016/0960-0760(91)90312-s

[53] Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 2009; 102(4):453-462. doi: 10.1093/bja/aep037

[54] Werner MF, Fraga D, Melo MC, Souza GE, Zampronio AR. Importance of the vagus nerve for fever and neutrophil migration induced by intraperitoneal LPS injection. Inflamm Res. 2003; 52(7):291-296. doi: 10.1007/s00011-003-1174-8

[55] Jiang H, Ling Z, Zhang Y, et al. Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun. 2015; 48:186-194. doi: 10.1016/j.bbi.2015.03.016

[56] Amyot J, Semache M, Ferdaoussi M, Fontes G, Poitout V. Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via toll-like receptor-4 and NF-kappaB signalling. PLoS One. 2012; 7(4):e36200. doi: 10.1371/journal.pone.0036200

[57] Yang X, Chen J, Wang J, et al. Very-low-density lipoprotein receptor-enhanced lipid metabolism in pancreatic stellate cells promotes pancreatic fibrosis. Immunity. 2022; 55(7):1185-1199.e8. doi: 10.1016/j.immuni.2022.06.001