AbstractPrevious genetically informed studies have uncovered likely causal relationships between mental health problems and self-harm but resulting causal estimates may be biased due to unmediated pleiotropy. By fitting Mendelian Randomization - Direction of Causation (MR-DoC) models that explicitly model pleiotropy, we investigated the effect of four quantitatively measured mental health problems - major depressive disorder (MDD), schizophrenia, attention-deficit hyperactivity disorder (ADHD), and insomnia, on non-suicidal self-harm (NSSH) and suicidal self-harm (SSH), separately. We used data of 12,723 twins (56.6% females) in the Twins Early Development Study. Besides substantial pleiotropy, we found effects from child-rated depressive symptoms to both NSSH (β = 0.194, 95% CIs: 0.131, 0.257) and SSH (β = 0.210, 95% CIs: 0.125, 0.295). Similarly, effects flowed from parent-rated depressive symptoms to NSSH (β = 0.092, 95% CIs: 0.004, 0.181) and SSH (β = 0.165, 95% CIs: 0.051, 0.281). We did not find evidence of aetiological difference between NSSH and SSH.