ArticlePLoS genetics2011
Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
Article in PLoS genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 4 of them syntheses that pooled it.
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Who cites it
98 citing papers in PubMed, 4 syntheses or guidelines pooled it, 174 citations in OpenAlex.
- Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.Nature genetics · 2017Pooled it
- Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer.International journal of cancer · 2016Pooled it
- Methods for association analysis and meta-analysis of rare variants in families.Genetic epidemiology · 2015Pooled it
- Efficiency of trans-ethnic genome-wide meta-analysis and fine-mapping.European journal of human genetics : EJHG · 2012Pooled it
- Large-Scale Phenome-Wide Association Study ofCirculation. Genomic and precision medicine · 2018Trial
- Topological stratification of continuous genetic variation in large biobanks.PLoS genetics · 2026Article
- Genome-wide association study identifies novel and confirms established loci associated with serum lipids levels in Brazilians.Human genetics · 2026Article
- Influence of Common Gene Variants on Lipid Levels and Risk of Coronary Heart Disease in Afro-Caribbeans.International journal of molecular sciences · 2024Article
- Article
- Advances in understanding the genetic architecture of antibody response to paratuberculosis in sheep by heritability estimate and LDLA mapping analyses and investigation of candidate regions using sequence-based data.Genetics, selection, evolution : GSE · 2024Article
- Association of PCSK9 levels and genetic polymorphisms with stroke recurrence and functional outcome after acute ischemic stroke.Annals of translational medicine · 2022Article
- Association of protein function-altering variants with cardiometabolic traits: the strong heart study.Scientific reports · 2022Article
- A statistical boosting framework for polygenic risk scores based on large-scale genotype data.Frontiers in genetics · 2022Article
- The flashfm approach for fine-mapping multiple quantitative traits.Nature communications · 2021Article
- Translating genetic association of lipid levels for biological and clinical application.Cardiovascular drugs and therapy · 2021Review
- Genome-wide association studies in Samoans give insight into the genetic architecture of fasting serum lipid levels.Journal of human genetics · 2021Article
- Tractor uses local ancestry to enable the inclusion of admixed individuals in GWAS and to boost power.Nature genetics · 2021Article
- Rare Coding Variants Associated with Breast Cancer.Advances in experimental medicine and biology · 2021Article
- Analysis in case-control sequencing association studies with different sequencing depths.Biostatistics (Oxford, England) · 2020Article
- Beyond large-effect loci: large-scale GWAS reveals a mixed large-effect and polygenic architecture for age at maturity of Atlantic salmon.Genetics, selection, evolution : GSE · 2020Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 9 institutions in 4 countries.
Funding
Abstract
Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci.
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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.