Type 2 diabetes is causally associated with depression: a Mendelian randomization analysis

Abstract

Type 2 diabetes (T2D) has been associated with a high prevalence of depression. We aimed to determine the causal relation by performing a Mendelian randomization (MR) study using 34 T2D risk genetic variants validated in East Asians as the instrumental variable (IV). An MR analysis was performed involving 11 506 participants from a large longitudinal study. The T2D genetic risk score (GRS) was built using the 34 typical T2D common variants. We used T2D_GRS as the IV estimator and performed inverse-variance weighted (IVW) and Egger MR analysis. The T2D_GRS was found to be associated with depression with an OR of 1.21 (95% CI: 1.07–1.37) after adjustments for age, sex, body mass index, current smoking and drinking, physical activity, education, and marital status. Using T2D_GRS as the IV, we similarly found a causal relationship between genetically determined T2D and depression (OR: 1.84, 95% CI: 1.25–2.70). Though we found no association between the combined effect of the genetic IVs for T2D and depression with Egger MR (OR: 0.95, 95% CI: 0.42–2.14), we found an association for T2D and depression with IVW (OR: 1.75, 95% CI: 1.31–2.46) after excluding pleiotropic SNPs. Overall, the MR analyses provide evidence inferring a potential causal relationship between T2D and depression.

Keywords

causal modeling / depression / Mendelian randomization / type 2 diabetes

References

[1] Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013; 382(9904):1575–1586

[2] Ferrari AJ, Charlson FJ, Norman RE, Patten SB, Freedman G, Murray CJ, Vos T, Whiteford HA. Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010. PLoS Med 2013; 10(11): e1001547

[3] World Health Organization. Depression and Other Common Mental Disorders: Global Health Estimates. 2017. Available from

[4] Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic review. J Affect Disord 2012; 142(Suppl): S8–S21

[5] Nanditha A, Ma RC, Ramachandran A, Snehalatha C, Chan JC, Chia KS, Shaw JE, Zimmet PZ. Diabetes in Asia and the Pacific: implications for the Global Epidemic. Diabetes Care 2016; 39(3): 472–485

[6] Xu Y, Wang L, He J, Bi Y, Li M, Wang T, Wang L, Jiang Y, Dai M, Lu J, Xu M, Li Y, Hu N, Li J, Mi S, Chen CS, Li G, Mu Y, Zhao J, Kong L, Chen J, Lai S, Wang W, Zhao W, Ning G; 2010 China Noncommunicable Disease Surveillance Group. Prevalence and control of diabetes in Chinese adults. JAMA 2013; 310(9): 948–959

[7] Black SA, Markides KS, Ray LA. Depression predicts increased incidence of adverse health outcomes in older Mexican Americans with type 2 diabetes. Diabetes Care 2003; 26(10): 2822–2828

[8] Anderson BJ, Edelstein S, Abramson NW, Katz LE, Yasuda PM, Lavietes SJ, Trief PM, Tollefsen SE, McKay SV, Kringas P, Casey TL, Marcus MD. Depressive symptoms and quality of life in adolescents with type 2 diabetes: baseline data from the TODAY study. Diabetes Care 2011; 34(10): 2205–2207

[9] Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over the lifespan: a meta-analysis. Diabetes Care 2008; 31(12): 2383–2390

[10] Golden SH, Lazo M, Carnethon M, Bertoni AG, Schreiner PJ, Diez Roux AV, Lee HB, Lyketsos C. Examining a bidirectional association between depressive symptoms and diabetes. JAMA 2008; 299(23): 2751–2759

[11] Nouwen A, Winkley K, Twisk J, Lloyd CE, Peyrot M, Ismail K, Pouwer F; European Depression in Diabetes (EDID) Research Consortium. Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis. Diabetologia 2010; 53(12): 2480–2486

[12] Rotella F, Mannucci E. Diabetes mellitus as a risk factor for depression. A meta-analysis of longitudinal studies. Diabetes Res Clin Pract 2013; 99(2): 98–104

[13] Sun JC, Xu M, Lu JL, Bi YF, Mu YM, Zhao JJ, Liu C, Chen LL, Shi LX, Li Q, Yang T, Yan L, Wan Q, Wu SL, Liu Y, Wang GX, Luo ZJ, Tang XL, Chen G, Huo YN, Gao ZN, Su Q, Ye Z, Wang YM, Qin GJ, Deng HC, Yu XF, Shen FX, Chen L, Zhao LB, Wang TG, Lai SH, Li DH, Wang WQ, Ning G; Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal (REACTION) Study group. Associations of depression with impaired glucose regulation, newly diagnosed diabetes and previously diagnosed diabetes in Chinese adults. Diabet Med 2015; 32(7): 935–943

[14] Harrison SC, Holmes MV, Humphries SE. Mendelian randomisation, lipids, and cardiovascular disease. Lancet 2012; 380(9841): 543–545

[15] Xu M, Huang Y, Xie L, Peng K, Ding L, Lin L, Wang P, Hao M, Chen Y, Sun Y, Qi L, Wang W, Ning G, Bi Y. Diabetes and risk of arterial stiffness: a Mendelian randomization analysis. Diabetes 2016; 65(6): 1731–1740

[16] 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

[17] Palmer TM, Lawlor DA, Harbord RM, Sheehan NA, Tobias JH, Timpson NJ, Davey Smith G, Sterne JA. Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 2012; 21(3): 223–242

[18] Liu S, Song Y. Building genetic scores to predict risk of complex diseases in humans: is it possible? Diabetes 2010; 59(11): 2729–2731

[19] Bi Y, Lu J, Wang W, Mu Y, Zhao J, Liu C, Chen L, Shi L, Li Q, Wan Q, Wu S, Yang T, Yan L, Liu Y, Wang G, Luo Z, Tang X, Chen G, Huo Y, Gao Z, Su Q, Ye Z, Wang Y, Qin G, Deng H, Yu X, Shen F, Chen L, Zhao L, Zhang J, Sun J, Dai M, Xu M, Xu Y, Chen Y, Lai S, Bloomgarden ZT, Li D, Ning G. Cohort profile: risk evaluation of cancers in Chinese diabetic individuals: a longitudinal (REACTION) study. J Diabetes 2014; 6(2): 147–157

[20] Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16(9): 606–613

[21] Löwe B, Kroenke K, Herzog W, Gräfe K. Measuring depression outcome with a brief self-report instrument: sensitivity to change of the Patient Health Questionnaire (PHQ-9). J Affect Disord 2004; 81(1): 61–66

[22] Pignone MP, Gaynes BN, Rushton JL, Burchell CM, Orleans CT, Mulrow CD, Lohr KN. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 136(10): 765–776

[23] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28(7): 412–419

[24] Cersosimo E, Solis-Herrera C, Trautmann ME, Malloy J, Triplitt CL. Assessment of pancreatic β-cell function: review of methods and clinical applications. Curr Diabetes Rev 2014; 10(1): 2–42

[25] Hagströmer M, Oja P, Sjöström M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr 2006; 9(6): 755–762

[26] Xu M, Bi Y, Huang Y, Xie L, Hao M, Zhao Z, Xu Y, Lu J, Chen Y, Sun Y, Qi L, Wang W, Ning G. Type 2 diabetes, diabetes genetic score and risk of decreased renal function and albuminuria: a Mendelian randomization study. EBioMedicine 2016; 6: 162–170

[27] Cho YS, Lee JY, Park KS, Nho CW. Genetics of type 2 diabetes in East Asian populations. Curr Diab Rep 2012; 12(6): 686–696

[28] Kato N. Insights into the genetic basis of type 2 diabetes. J Diabetes Investig 2013; 4(3): 233–244

[29] Cho YS, Chen CH, Hu C, Long J, Ong RT, Sim X, Takeuchi F, Wu Y, Go MJ, Yamauchi T, Chang YC, Kwak SH, Ma RC, Yamamoto K, Adair LS, Aung T, Cai Q, Chang LC, Chen YT, Gao Y, Hu FB, Kim HL, Kim S, Kim YJ, Lee JJ, Lee NR, Li Y, Liu JJ, Lu W, Nakamura J, Nakashima E, Ng DP, Tay WT, Tsai FJ, Wong TY, Yokota M, Zheng W, Zhang R, Wang C, So WY, Ohnaka K, Ikegami H, Hara K, Cho YM, Cho NH, Chang TJ, Bao Y, Hedman ÅK, Morris AP, McCarthy MI; DIAGRAM Consortium; MuTHER Consortium,Takayanagi R, Park KS, Jia W, Chuang LM, Chan JC, Maeda S, Kadowaki T, Lee JY, Wu JY, Teo YY, Tai ES, Shu XO, Mohlke KL, Kato N, Han BG, Seielstad M. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 2012; 44(1): 67–72

[30] Balding DJ. A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7(10): 781–791

[31] 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

[32] Samaan Z, Garasia S, Gerstein HC, Engert JC, Mohan V, Diaz R, Anand SS, Meyre D. Lack of association between type 2 diabetes and major depression: epidemiologic and genetic evidence in a multiethnic population. Transl Psychiatry 2015; 5(8): e618

[33] Clarke TK, Obsteter J, Hall LS, Hayward C, Thomson PA, Smith BH, Padmanabhan S, Hocking LJ, Deary IJ, Porteous DJ, McIntosh AM. Investigating shared aetiology between type 2 diabetes and major depressive disorder in a population based cohort. Am J Med Genet B Neuropsychiatr Genet 2017; 174(3): 227–234

[34] Wium-Andersen MK, Ørsted DD, Nordestgaard BG. Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression. Int J Epidemiol 2015; 44(2): 566–577

[35] Wium-Andersen MK, Ørsted DD, Tolstrup JS, Nordestgaard BG. Increased alcohol consumption as a cause of alcoholism, without similar evidence for depression: a Mendelian randomization study. Int J Epidemiol 2015; 44(2): 526–539

[36] Hartwig FP, Bowden J, Loret de Mola C, Tovo-Rodrigues L, Davey Smith G, Horta BL. Body mass index and psychiatric disorders: a Mendelian randomization study. Sci Rep 2016; 6(1): 32730

[37] Moulton CD, Pickup JC, Ismail K. The link between depression and diabetes: the search for shared mechanisms. Lancet Diabetes Endocrinol 2015; 3(6): 461–471

[38] U.S. Preventive Services Task Force. Screening for depression: recommendations and rationale. Ann Intern Med 2002; 136(10): 760–764

[39] Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry 2010; 32(4): 345–359

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature