biostudies-literatureHarroud ANIMH NIH HHS2077-2084https://www.ebi.ac.uk/biostudies/studies/S-EPMC8364919biostudies-literatureUnknown27(13)<h4>Background</h4>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.<h4>Objective</h4>The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR).<h4>Methods</h4>We selected genetic instruments associated with risk of MDD (<i>n</i> = 660,937 cases; 1,453,489 controls) and MS (<i>n</i> = 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.<h4>Results</h4>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).<h4>Conclusion</h4>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.Multiple sclerosis (Houndmills, Basingstoke, England)Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.PMC8364919K01 MH121582Marrie RAHarroud ALu YFitzgerald KCKowalec KPatel MSalter AfalseMendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.<h4>Background</h4>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.<h4>Objective</h4>The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR).<h4>Methods</h4>We selected genetic instruments associated with risk of MDD (<i>n</i> = 660,937 cases; 1,453,489 controls) and MS (<i>n</i> = 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.<h4>Results</h4>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).<h4>Conclusion</h4>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.2021-01-01T00:00:00Z2021 Nov2024-11-13T05:17:50.252Z2024-11-13T05:17:50.252ZS-EPMC83649193359123010.1177/1352458521993075