Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration

Objective: Lipoprotein(a) (Lp[a]) is associated with coronary artery disease (CAD) but also to LDL (low-density lipoprotein) cholesterol. The genetic architecture of Lp(a) remains incompletely understood, as well its independence cholesterol in association CAD. We investigated the determinants concentrations a large prospective multiethnic cohort. tested for potential causality between genetically determined higher and CAD using multivariable Mendelian randomization strategy. Approach Results: studied 371 212 participants UK Biobank available genome-wide data. Genome-wide analyses confirmed 2 known identified 37 novel loci ( P <5×10 ?8 ) Lp(a). Testing these instrumental variables an independent cohort 60 801 cases 123 504 controls, each SD elevated conferred 1.30 ([95% CI, 1.20–1.41] =5.53×10 ? 11 odds Importantly, this was Genetic fine-mapping LPA gene region 15 causal variants. This included rare missense variant (rs41267813[A]) lower concentration. observed strong interaction rs41267813 rs10455872 on concentrations, indicating protective effect rs41267813(A). Conclusions: study supports cholesterol–independent link A locus appears be people increasing rs10455872. In search therapeutic targets Lp(a), future work should focus understanding functional consequences variant.