ArticlePLoS genetics2012
Knowledge-driven analysis identifies a gene-gene interaction affecting high-density lipoprotein cholesterol levels in multi-ethnic populations.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- Detecting epistasis within chromatin regulatory circuitry reveals CAND2 as a novel susceptibility gene for obesity.International journal of obesity (2005) · 2019Pooled it
- Analysis of gene-gene interactions among common variants in candidate cardiovascular genes in coronary artery disease.PloS one · 2015Trial
- Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibits apoB reduction after statin-fenofibric acid therapy in individuals with mixed dyslipidemia.Journal of lipid research · 2012Trial
- Multivariate Genome-Wide Association Analysis Identifies Genetic Susceptibility Loci for Metabolic Syndrome in the Korean Genome and Epidemiology Study.International journal of molecular sciences · 2026Article
- A biobank-scale test of marginal epistasis reveals genome-wide signals of polygenic interaction effects.Nature genetics · 2025Article
- Identification of epistatic SNP combinations in rheumatoid arthritis using LAMPLINK and Japanese cohorts.Journal of human genetics · 2024Article
- BridGE: a pathway-based analysis tool for detecting genetic interactions from GWAS.Nature protocols · 2024Review
- Evaluation of Breeding Values and Variance Components of Birth and Weaning Weights in the Holstein Cows Herd Based on Genetic Information.Archives of Razi Institute · 2022Article
- Genetic Dissection of Epistatic Interactions Contributing Yield-Related Agronomic Traits in Rice Using the Compressed Mixed Model.Plants (Basel, Switzerland) · 2022Article
- Functional Haplotype ofGenes · 2021Article
- Genetics of Familial Hypercholesterolemia: New Insights.Frontiers in genetics · 2020Review
- Discovering genetic interactions bridging pathways in genome-wide association studies.Nature communications · 2019Article
- Pleiotropic association of LIPC variants with lipid and urinary 8-hydroxy deoxyguanosine levels in a Taiwanese population.Lipids in health and disease · 2019Article
- Candidate Variants for Additive and Interactive Effects on Bioenergy Traits in Switchgrass (The plant genome · 2018Article
- The search for gene-gene interactions in genome-wide association studies: challenges in abundance of methods, practical considerations, and biological interpretation.Annals of translational medicine · 2018Article
- Review
- The role of gene polymorphisms in endometriosis.Molecular medicine reports · 2017Article
- Genetic associations with lipoprotein subfraction measures differ by ethnicity in the multi-ethnic study of atherosclerosis (MESA).Human genetics · 2017Article
- Dissection of additive, dominance, and imprinting effects for production and reproduction traits in Holstein cattle.BMC genomics · 2017Article
- Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 1 country.
Funding
Abstract
Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene-gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein-protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P(c) = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene-gene interaction in the European American cohorts from the Framingham Heart Study (P(c) = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P(c) = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P(c) = 0.004) and in the Hispanic American sample from MESA (P(c) = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene-gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.