TY - JOUR
T1 - Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels-Brief Report
AU - Hoekstra, Mary
AU - Chen, Hao Yu
AU - Rong, Jian
AU - Dufresne, Line
AU - Yao, Jie
AU - Guo, Xiuqing
AU - Tsai, Michael Y.
AU - Tsimikas, Sotirios
AU - Post, Wendy S.
AU - Vasan, Ramachandran S.
AU - Rotter, Jerome I.
AU - Larson, Martin G.
AU - Thanassoulis, George
AU - Engert, James C.
N1 - Publisher Copyright:
© 2020 American Heart Association, Inc.
PY - 2020/10/29
Y1 - 2020/10/29
N2 - OBJECTIVE: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. 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 at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant 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 the LPA locus (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 identified APOH as a novel locus for Lp(a) in individuals of European ancestry.
AB - OBJECTIVE: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. 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 at LPA, APOE, and CETP, we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant 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 the LPA locus (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 identified APOH as a novel locus for Lp(a) in individuals of European ancestry.
KW - Atherosclerosis
KW - Cardiovascular diseases
KW - Genome-wide association study
KW - Lipoprotein(a)
KW - Risk factors
UR - http://www.scopus.com/inward/record.url?scp=85098199766&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098199766&partnerID=8YFLogxK
U2 - 10.1161/atvbaha.120.314965
DO - 10.1161/atvbaha.120.314965
M3 - Article
C2 - 33115273
AN - SCOPUS:85098199766
SN - 1079-5642
VL - 41
SP - 458
EP - 464
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 1
ER -