Second, sample overlap in two-sample MR can bias results towards the observational estimate (Burgess et al., 2015). There was some sample overlap between the major depression GWAS (Wray et al., 2018) and the UK Biobank (used to derive the lifetime smoking instrument and included in the smoking initiation GWAS) meaning that the effects could be inflated. Therefore, a sensitivity analysis was conducted using a previous GWAS of major depression (Ripke et al., 2013) which showed the same direction of effect despite lower power. This gives us confidence in the bi-directional effects of smoking and depression, despite sample overlap. This sensitivity analysis also addresses recent concerns over the specificity of the most recent GWAS for major depression (Cai et al., 2019). Comparing self-reported ‘seeking help for depression’ with DSM-diagnosed MDD yielded different results (Cai et al., 2019). However, the earlier GWAS of depression did use Diagnostic and statistical manual diagnosed cases only (Ripke et al., 2013) and showed the same direction of effect despite lower power.
