A novel variant associated with HDL-C levels by modifying DAGLB expression levels: An annotation-based genome-wide association study

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 (P = 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.

Genome-wide association meta-analysis yields 20 loci associated with gallstone disease

“…Of note is that a missense variant Gln535Arg in DAGLB (rs2303361[C]), encoding diacylglycerol lipase beta, associates with an increased risk of gallstone disease (OR = 1.06 [1.04–1.08], P = 4.7 × 10 –8 ). The variant is in strong LD ( r 2 = 0.95) with the intron variant rs1880118[C] that was recently reported to associate with increased HDL cholesterol levels and increased DAGLB expression in subcutaneous adipose tissue 42 . We replicate the association of rs1880118[C] with increased HDL cholesterol in our data (effect = 0.15 SD [0.10–0.20], P = 2.4 × 10 –9 ).…”

Identification of hub genes significantly linked to tuberous sclerosis related-epilepsy and lipid metabolism via bioinformatics analysis

“…A corresponding reduction in lipopolysaccharide-induced TNF-α release was also observed. These findings suggest a role for DAGLB in the lipid network that regulates the inflammatory response in macrophages ( 42 ).…”

Integration of GWAS and eQTL Analysis to Identify Risk Loci and Susceptibility Genes for Gastric Cancer

“…In DAGLB knockout mice, DAGLβ inhibition can reduce 2-arachidonoylglycerol and arachidonic acid and eicosanoids in macrophages (Hsu et al, 2012). A recent GWAS reported a novel variant with HDL-C levels by modifying expression of DAGLB (Zhou et al, 2018). To the best of our knowledge, metabolism of lipids, especially arachidonic acid, has been proved to be an important regulator in the process of inflammation and cancer (Walduck et al, 2009).…”