The DOI matches its Crossref record; 12 of the 12 references it cites were found in a registry or an index.
Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability
Open accessAbstract
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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Cites
Finding the missing heritability of complex diseases
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Self-citationBiological, clinical and population relevance of 95 loci for blood lipids
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Self-citationSequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease
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A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants
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Self-citationLocusZoom: regional visualization of genome-wide association scan results
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Self-citationNewly identified loci that influence lipid concentrations and risk of coronary artery disease
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Self-citationFrom noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus
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Uncovering the roles of rare variants in common disease through whole-genome sequencing
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Rare Variants Create Synthetic Genome-Wide Associations
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Cited by
An integrated map of genetic variation from 1,092 human genomes
The 1000 Genomes Project Consortium (2012) · Nature · doi:10.1038/nature11632 · Cited by 7,711
Willer (2013) · doi:10.1038/ng.2797 · Cited by 2,983
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Beyond GWASs: Illuminating the Dark Road from Association to Function
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Metadata
- Authors
- Sanna, S., Li, B., Mulas, A., Sidore, C., Kang, H. M., Jackson, A. U., Piras, M. G., Usala, G., Maninchedda, G., Sassu, A., Serra, F., Palmas, M. A., Wood, W. H., Njølstad, I., Laakso, M., Hveem, K., Tuomilehto, J., Lakka, T. A., Rauramaa, R., Boehnke, M., Cucca, F., Uda, M., Schlessinger, D., Nagaraja, R., & Abecasis, G. R.
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-07-28
- Volume
- 7
- Issue
- 7
- Pages
- e1002198
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- OpenAlex
- W2121662608
- Cited by
- 166
- References
- 12
- FWCI
- 16.08
- Type
- journal article
- Language
- en
- Open access
- gold
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- Sanna, S., Li, B., Mulas, A., Sidore, C., Kang, H. M., Jackson, A. U., Piras, M. G., Usala, G., Maninchedda, G., Sassu, A., Serra, F., Palmas, M. A., Wood, W. H., Njølstad, I., Laakso, M., Hveem, K., Tuomilehto, J., Lakka, T. A., Rauramaa, R., . . . Abecasis, G. R. (2011). Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability. PLoS Genetics. https://doi.org/10.1371/journal.pgen.1002198
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