Abstract
Although numbers of genome-wide association studies (GWAS) have been performed for serum lipid levels, limited heritability has been explained. Studies showed that combining data from GWAS and expression quantitative trait loci (eQTLs) signals can both enhance the discovery of trait-associated SNPs and gain a better understanding of the mechanism. We performed an annotation-based, multistage genome-wide screening for serum-lipid-level-associated loci in totally 6863 Han Chinese. A serum high-density lipoprotein cholesterol (HDL-C) associated variant rs1880118 (hg19 chr7:g. 6435220G>C) was replicated (Pcombined = 1.4E-10). rs1880118 was associated with DAGLB (diacylglycerol lipase, beta) expression levels in subcutaneous adipose tissue (P = 5.9E-42) and explained 47.7% of the expression variance. After the replication, an active segment covering variants tagged by rs1880118 near 5′ of DAGLB was annotated using histone modification and transcription factor binding signals. The luciferase report assay revealed that the segment containing the minor alleles showed increased transcriptional activity compared with segment contains the major alleles, which was consistent with the eQTL analyses. The expression-trait association tests indicated the association between the DAGLB and serum HDL-C levels using gene-based approaches called “TWAS” (P = 3.0E-8), “SMR” (P = 1.1E-4), and “Sherlock” (P = 1.6E-6). To summarize, we identified a novel HDL-C-associated variant which explained nearly half of the expression variance of DAGLB. Integrated analyses established a genotype-gene-phenotype three-way association and expanded our knowledge of DAGLB in lipid metabolism.
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Acknowledgements
This work was supported by the National Key Technology R & D Program of China (2009BAI80B02, 2012BAI02B03), the 973 Program (2015CB559100), the National Natural Science Foundation of China (81172755, 31325014, 81421061, 81701321), the 111 Project (B13026), the Program for Zhejiang Leading Team of Science and Technology Innovation (2010R50050), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents, the Program of Shanghai Academic Research Leader (15XD1502200), the National Program for Support of Top-Notch Young Professionals. We would like to acknowledge all the staff and participants in this study for their important contribution.
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Zhou, D., Zhang, D., Sun, X. et al. A novel variant associated with HDL-C levels by modifying DAGLB expression levels: An annotation-based genome-wide association study. Eur J Hum Genet 26, 838–847 (2018). https://doi.org/10.1038/s41431-018-0108-4
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DOI: https://doi.org/10.1038/s41431-018-0108-4
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