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Pairwise effects between lipid GWAS genes modulate lipid plasma levels and cellular uptake
Magdalena Zimoń1,2, Yunfeng Huang3, Anthi Trasta1,2
1Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/EMBL, Heidelberg, Germany.
Nature Communications
|November 6, 2021
Summary
Investigating complex traits, this study combined human genetics and RNAi to analyze gene pairs affecting lipid levels. Key gene pairs, like APOB with PCSK9 or LPL, show additive effects, informing lipid-lowering therapies.
Area of Science:
- Genetics and Genomics
- Molecular Biology
- Cardiovascular Research
Background:
- Complex traits involve multiple genes, making individual gene pair contributions difficult to study.
- Human genetics requires large populations, and model system findings may not apply to humans.
Purpose of the Study:
- To systematically test pairwise additive effects (AEs) and genetic interactions (GIs) between 30 lipid genome-wide association studies (GWAS) genes.
- To identify gene pairs modulating plasma and cellular lipid levels.
- To nominate potential drug target pairs for combination therapies.
Main Methods:
- Utilized combinatorial RNAi (coRNAi) alongside human genetics.
- Performed gene-based burden tests on 240,970 exomes.
- Analyzed additive effects and genetic interactions for specific gene pairs.
Main Results:
- Identified additive effects for APOB with PCSK9 or LPL in human "double knock-outs".
- Discovered overlapping AEs for 12 additional gene pairs.
- Observed overlapping GIs for TOMM40/APOE with SORT1 and NCAN.
Conclusions:
- Distinct gene pairs primarily modulate lipid levels through additive effects.
- The study nominates potential drug target pairs for enhanced lipid-lowering combination therapies.
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