Abstract
Genome-wide association studies (GWASs) have implicated ∼380 genetic loci for plasma lipid regulation. However, these loci only explain 17–27% of the trait variance, and a comprehensive understanding of the molecular mechanisms has not been achieved. In this study, we utilized an integrative genomics approach leveraging diverse genomic data from human populations to investigate whether genetic variants associated with various plasma lipid traits, namely, total cholesterol, high and low density lipoprotein cholesterol (HDL and LDL), and triglycerides, from GWASs were concentrated on specific parts of tissue-specific gene regulatory networks. In addition to the expected lipid metabolism pathways, gene subnetworks involved in “interferon signaling,” “autoimmune/immune activation,” “visual transduction,” and “protein catabolism” were significantly associated with all lipid traits. In addition, we detected trait-specific subnetworks, including cadherin-associated subnetworks for LDL; glutathione metabolism for HDL; valine, leucine, and isoleucine biosynthesis for total cholesterol; and insulin signaling and complement pathways for triglyceride. Finally, by using gene-gene relations revealed by tissue-specific gene regulatory networks, we detected both known (e.g., APOH, APOA4, and ABCA1) and novel (e.g., F2 in adipose tissue) key regulator genes in these lipid-associated subnetworks. Knockdown of the F2 gene (coagulation factor II, thrombin) in 3T3-L1 and C3H10T1/2 adipocytes altered gene expression of Abcb11, Apoa5, Apof, Fabp1, Lipc, and Cd36; reduced intracellular adipocyte lipid content; and increased extracellular lipid content, supporting a link between adipose thrombin and lipid regulation. Our results shed light on the complex mechanisms underlying lipid metabolism and highlight potential novel targets for lipid regulation and lipid-associated diseases.
Highlights
Lipid metabolism is vital for organisms as it provides energy as well as essential materials such as membrane components and signaling molecules for basic cellular functions
Identification of pathways and gene coexpression modules associated with lipid traits To asses biological pathway enrichment for the four lipid traits with Global Lipids Genetics Consortium (GLGC) genome-wide association study (GWAS), we curated a total of 4,532 gene sets including 2,705 tissue-specific coexpression modules and 1,827 canonical pathways from Reactome, Biocarta and Kyoto Encyclopedia of Genes and Genomes (KEGG)
Four predefined positive control gene sets for high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL), total cholesterol (TC), and TG were created based on candidate genes curated from the GWAS catalog [57]
Summary
Lipid metabolism is vital for organisms as it provides energy as well as essential materials such as membrane components and signaling molecules for basic cellular functions. Various pathway- and network-based approaches to analyzing GWAS datasets have been developed [18, 22,23,24] and demonstrated to be powerful to capture both the missing heritability and the molecular mechanisms of many human diseases or quantitative phenotypes [18, 23, 25, 26] For these reasons, integrating genetic signals of blood lipids with multitissue multiomics datasets that carry important functional information may provide a better understanding of the molecular mechanisms responsible for lipid regulation as well as the associated human diseases. The integrative framework comprises four main parts (Fig. 1): 1) Marker Set Enrichment Analysis (MSEA) where GWAS, functional genome, and pathways or
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