The consistent evidence we identify across two genetic variants of HFE (rs1800562 and rs1799945) and one variant of TMPRSS6 (rs855791) for a causal effect of higher iron status on lowering risk of both hypercholesterolemia and gallbladder cholesterolosis implicates a mechanism in which high iron status more generally affects cholesterol synthesis. Here, HFE is linked to familial hypercholesterolemia.