This is consistent with previous work reporting that R227W had a significantly weaker effect on stroke than other curated pathogenic HTRA1 variants.29 Follow-up analyses demonstrated that the gene-level association of HTRA1 with coronary artery disease was driven in large part by R227W, with evidence of significant heterogeneity between variant-level estimates for R227W and the rest of the predicted damaging missense variants (Cochrane test of heterogeneity, PHet=0.03). This evidence concerns the gene HTRA1 and coronary artery disorder.