Chenhui Zhang
Jinxiu Shi
Hong Wu
Wei Huang
aDepartment of Genetics, Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai and Shanghai Academy of Science and Technology, Shanghai 200025, China
bDepartment of Cardiology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, China
More InformationCorresponding author: E-mail address: shouwh@chgc.sh.cn (Weihua Shou);E-mail address: huangwei@chgc.sh.cn (Wei Huang)
Publish Date:2020-12-25
Abstract
Abstract
The unusual chromosome 11q23.3 harboring the apolipoprotein (APO) gene cluster has been well documented for its essential roles in plasma lipid-related traits and atherosclerotic cardiovascular diseases. However, its genetic architecture and the potential biological mechanisms underlying complex phenotypes have not been well assessed. We conducted a study for this target region in a Han Chinese population through a stepwise forward framework based on massive parallel sequencing, association analyses, genetic fine mapping, and functional interpretation. The present study identified new meaningful genetic associations that were not simply determined by statistical significance. In addition to the APOA5 gene, we found robust evidence of the genetic commitments of APOC3 and APOA1 to blood lipids. Several variants with high confidence were prioritized along with the potential biological mechanism interpretations in the wake of adaptive fine-mapping analyses. rs2849174 in the APOC3 enhancer was discovered with an unrivaled posterior probability of causality for triglyceride levels and could mediateAPOC3 expression through enhancer activity modulated by a combination of histone modifications and transcription factor accessibility. Similarly, multiple lines of evidence converged in favor of rs3741297 as a causal variant influencing high-density lipoprotein cholesterol. Our findings provided novel insights into this genomic locus in the Chinese population.Keywords: Blood lipids,
Coronary artery disease,
Genetic associations,
Progressive analyses for prioritizing,
Causal genetic factors
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