PIEZO1 and osteoporosis: We identified a previously undescribed gene-burden association in PIEZO1, a mechanosensing ion channel that is present in endothelial cells in vascular walls; LOF variants confer a nearly fivefold increased odds of varicose veins in carriers of heterozygous LOF variants in PIEZO1. We also identified a previously undescribed LOF burden association in MEPE, which is associated with decreased BMD and an approximately 2-fold increased odds of osteoporosis and 1.5-fold increased risk of fractures.