For example, rs3184504 is a well-known missense variant in SH2B3 that is associated with hundreds of traits at genome-wide significance.105 A subsequent MR analysis utilized a more biologically informed approach that identified genetic proxies for TNF-a signaling as cis variants near TNFRSF1A (encoding TNF receptor 1) that were associated with lower levels of CRP.106 This approach did not reveal significant associations with ischemic stroke risk in MEGASTROKE, though CIs were wide (OR 0.77, 95% CI 0.36–1.65). Here, TNF is linked to ischemic stroke.