Assessing and Adjusting for Selection Bias in Mendelian Randomization: the Effects of Body Mass Index, Education, and C-reactive Protein on Depression in UK Biobank.

Depression analyses in UK Biobank may be affected by selection bias due to incomplete participation in the optional Mental Health Questionnaire. We used one-sample Mendelian randomization (MR) to assess the causal effects of BMI, educational attainment (EA), and CRP on depression, applying inverse probability of selection weighting (IPW) and the instrumental variable for selection (IVsel) to adjust for selection into the MHQ sample. Sensitivity analyses included the use of psychiatrist consultation as a proxy outcome. MR analyses indicated that higher BMI increased the risk of depression (OR=1.09 [1.05, 1.13]), EA was protective (OR=0.81 [0.75, 0.88]), and there was limited evidence that CRP affected depression (OR=1.01 [0.92, 1.10]). Estimates obtained using IPW and IVsel were broadly consistent, although with IVsel estimates closer to the null, within BMI (ORIPW = 1.10 [1.05, 1.15], ORIVsel = 1.04 [1.02, 1.06]), EA (ORIPW = 0.81 [0.74, 0.88], ORIVsel = 0.93 [0.90, 0.96]) and CRP (ORIPW = 1.03 [0.92, 1.15], ORIVsel = 1.00 [0.97, 1.04]). Proxy outcome analyses suggested similar patterns of selection bias, supporting their utility for assessing potential bias in MHQ-restricted analyses. Bias-adjustment methods and sensitivity analyses provide a framework to assess the impact of selection bias in large cohort studies with optional components.