TY - JOUR
T1 - Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis
AU - Harroud, Adil
AU - Marrie, Ruth Ann
AU - Fitzgerald, Kathryn C.
AU - Salter, Amber
AU - Lu, Yi
AU - Patel, Mitulkumar
AU - Kowalec, Kaarina
N1 - Funding Information:
The authors thank the IMSGC and the PGC for access to their summary statistics data. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A.H. was supported by the NMSS-ABF Clinician Scientist Development Award from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada (FAN-1808-32256). R.A.M. was supported by the Waugh Family Chair in Multiple Sclerosis and a Manitoba Research Chair. K.C.F. was supported by the NMSS Career Transition Fellowship (TA-1805-31136) and NIH/NIMH K01 (1K01MH121582-01). K.K. received funding from the University of Manitoba.
Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A.H. was supported by the NMSS-ABF Clinician Scientist Development Award from the National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada (FAN-1808-32256). R.A.M. was supported by the Waugh Family Chair in Multiple Sclerosis and a Manitoba Research Chair. K.C.F. was supported by the NMSS Career Transition Fellowship (TA-1805-31136) and NIH/NIMH K01 (1K01MH121582-01). K.K. received funding from the University of Manitoba.
Publisher Copyright:
© The Author(s), 2021.
PY - 2021/11
Y1 - 2021/11
N2 - Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.
AB - Background: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. Objective: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). Methods: We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. Results: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90–1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99–1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09–1.65) and MDD (OR = 1.08, 95% CI = 1.01–1.15). Conclusion: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.
KW - Mendelian randomization
KW - Multiple sclerosis
KW - genetic epidemiology
KW - major depressive disorder
UR - http://www.scopus.com/inward/record.url?scp=85100900800&partnerID=8YFLogxK
U2 - 10.1177/1352458521993075
DO - 10.1177/1352458521993075
M3 - Article
C2 - 33591230
AN - SCOPUS:85100900800
SN - 1352-4585
VL - 27
SP - 2077
EP - 2084
JO - Multiple Sclerosis Journal
JF - Multiple Sclerosis Journal
IS - 13
ER -