Genome-Wide Association Study HighlightsAPOHas a Novel Locus for Lipoprotein(a) Levels

Abstract

Objective:Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at theLPAlocus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels.Approach and Results:We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance(P≤5×10-8). In addition to validating previous associations atLPA,APOE, andCETP, we identified a novel variant at theAPOHlocus, encoding β2GPI (beta2-glycoprotein I). TheAPOHvariant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081];P=2.8×10-13) and demonstrated a stronger effect after adjustment for variation at theLPAlocus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10];P=3.8×10-42). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28];P=0.0071).Conclusions:In a large-scale genome-wide association study of Lp(a) levels, we identifiedAPOHas a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.