ArticlePLoS genetics2013
RNAi-based functional profiling of loci from blood lipid genome-wide association studies identifies genes with cholesterol-regulatory function.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 57 citations in OpenAlex.
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- Circulating GDF-15: a biomarker for metabolic dysregulation and aging in people living with HIV.Frontiers in aging · 2024Article
- Equine Metabolic Syndrome: A Complex Disease Influenced by Multifactorial Genetic Factors.Genes · 2023Review
- Systematic elucidation of genetic mechanisms underlying cholesterol uptake.Cell genomics · 2023Article
- Systematic elucidation of genetic mechanisms underlying cholesterol uptake.bioRxiv : the preprint server for biology · 2023Article
- Impact of PCSK9, WDR12, CDKN2A, and CXCL12 Polymorphisms in Jordanian Cardiovascular Patients on Warfarin Responsiveness and Sensitivity.International journal of general medicine · 2021Article
- Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids.Nature communications · 2020Article
- TBL2 methylation is associated with hyper-low-density lipoprotein cholesterolemia: a case-control study.Lipids in health and disease · 2020Article
- An APOO Pseudogene on Chromosome 5q Is Associated With Low-Density Lipoprotein Cholesterol Levels.Circulation · 2018Article
- Non-coding RNAs in cardiovascular diseases: diagnostic and therapeutic perspectives.European heart journal · 2018Review
- Systematic RNA-interference in primary human monocyte-derived macrophages: A high-throughput platform to study foam cell formation.Scientific reports · 2018Article
- A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation.Scientific reports · 2018Article
- Systems Pharmacology Dissection of Cholesterol Regulation Reveals Determinants of Large Pharmacodynamic Variability between Cell Lines.Cell systems · 2017Article
- Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells.Human molecular genetics · 2016Article
- SUGP1 is a novel regulator of cholesterol metabolism.Human molecular genetics · 2016Article
- Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes.The Journal of biological chemistry · 2015Article
- The impact of low-frequency and rare variants on lipid levels.Nature genetics · 2015Article
- Next-generation gene discovery for variants of large impact on lipid traits.Current opinion in lipidology · 2015Review
- Systematic cell-based phenotyping of missense alleles empowers rare variant association studies: a case for LDLR and myocardial infarction.PLoS genetics · 2015Article
- Analysis of rs6725887 in the WD Repeat Protein 12 in Association with Coronary Artery Disease in Iranian Patients.International journal of molecular and cellular medicine · 2015Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genome-wide association studies (GWAS) are powerful tools to unravel genomic loci associated with common traits and complex human disease. However, GWAS only rarely reveal information on the exact genetic elements and pathogenic events underlying an association. In order to extract functional information from genomic data, strategies for systematic follow-up studies on a phenotypic level are required. Here we address these limitations by applying RNA interference (RNAi) to analyze 133 candidate genes within 56 loci identified by GWAS as associated with blood lipid levels, coronary artery disease, and/or myocardial infarction for a function in regulating cholesterol levels in cells. Knockdown of a surprisingly high number (41%) of trait-associated genes affected low-density lipoprotein (LDL) internalization and/or cellular levels of free cholesterol. Our data further show that individual GWAS loci may contain more than one gene with cholesterol-regulatory functions. Using a set of secondary assays we demonstrate for a number of genes without previously known lipid-regulatory roles (e.g. CXCL12, FAM174A, PAFAH1B1, SEZ6L, TBL2, WDR12) that knockdown correlates with altered LDL-receptor levels and/or that overexpression as GFP-tagged fusion proteins inversely modifies cellular cholesterol levels. By providing strong evidence for disease-relevant functions of lipid trait-associated genes, our study demonstrates that quantitative, cell-based RNAi is a scalable strategy for a systematic, unbiased detection of functional effectors within GWAS loci.
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