BACKGROUND: Both elevated and blunted cortisol responses have been associated with depression. Previous Mendelian randomization (MR) studies have largely ruled out cortisol as a cause of depression. Based on the attenuation hypothesis, this MR study used depression as exposure to assess whether cortisol might be a consequence and therefore a biomarker of depression. METHODS: Strong (P <
5 × 10 RESULTS: Using 133 SNPs as instruments, depression was inversely associated with morning plasma cortisol (β per log-odds of genetic liability to depression = -0.107 [95 % CI, -0.181 to -0.032]) in the CORNET consortium. Replication in the METSIM study (β = -0.203 [95 % CI, -0.367 to -0.040]) and CLSA cohort (β = -0.091 [95 % CI, -0.220 to 0.039]) showed consistent but not always significant associations. Multivariable MR and follow-up analysis incorporating colocalization supported these findings. CONCLUSIONS: Consistent with the attenuation hypothesis, blunted cortisol response appeared to be a consequence and potentially a biomarker of depression. Future studies are needed to provide more interpretable effect sizes and validate other biomarker measures.