Genome-wide association analysis and replication in 810,625 individuals with varicose veins
Ahmed W-U-R., Kleeman S., Ng M., Wang W., Auton A., Agee M., Aslibekyan S., Bell RK., Bryc K., Clark SK., Elson SL., Fletez-Brant K., Fontanillas P., Furlotte NA., Gandhi PM., Heilbron K., Hicks B., Hinds DA., Huber KE., Jewett EM., Jiang Y., Kleinman A., Lin K-H., Litterman NK., Luff MK., McCreight JC., McIntyre MH., McManus KF., Mountain JL., Mozaffari SV., Nandakumar P., Noblin ES., Northover CAM., O’Connell J., Petrakovitz AA., Pitts SJ., Poznik GD., Sathirapongsasuti JF., Shastri AJ., Shelton JF., Shringarpure S., Tian C., Tung JY., Tunney RJ., Vacic V., Wang X., Zare AS., Lee R., Handa A., Zondervan KT., Wiberg A., Furniss D.
AbstractVaricose veins affect one-third of Western society, with a significant subset of patients developing venous ulceration, costing $14.9 billion annually in the USA. Current management consists of either compression stockings, or surgical ablation for more advanced disease. Most varicose veins patients report a positive family history, and heritability is ~17%. We describe the largest two-stage genome-wide association study of varicose veins in 401,656 individuals from UK Biobank, and replication in 408,969 individuals from 23andMe (total 135,514 cases and 675,111 controls). Forty-nine signals at 46 susceptibility loci were discovered. We map 237 genes to these loci, several of which are biologically plausible and tractable to therapeutic targeting. Pathway analysis identified enrichment in extracellular matrix biology, inflammation, (lymph)angiogenesis, vascular smooth muscle cell migration, and apoptosis. Using a polygenic risk score (PRS) derived in an independent cohort, we demonstrate its predictive utility and correlation with varicose veins surgery.