We also detected evidence for a fully or partially genetically causal effect of hypothyroidism on MI (Table 1). Although hypothyroidism is not as well-established a cardiovascular risk factor as high LDL, its genetic correlation with MI is comparable (Table 1), and this effect is mechanistically plausible[40,41]. While this result was robust in the conditional analysis (Supplementary Table 13), and there was no strong evidence for a genetically causal effect of hypothyroidism on lipid traits (Supplementary Table 12), it is possible that this effect is mediated by lipid traits. A recent MR study of thyroid hormone levels, at ~20 × lower sample size than the present study, provided evidence for a genetically causal effect on LDL but not CAD [42]. On the other hand, clinical trials have demonstrated that treatment of subclinical hypothyroidism leads to improvement in several cardiovascular risk factors [43-47]. We also detected evidence for a fully or partially genetically causal effect of hypothyroidism on T2D (Supplementary Table 11), consistent with a longitudinal association between subclinical hypothyroidism and diabetes incidence [48], as well as an effect of thyroid hormone withdrawal on glucose disposal in athyreotic patients [49].
