Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability

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...

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Vydané v:	PLoS genetics Ročník 7; číslo 7; s. e1002198
Hlavní autori:	Sanna, Serena, Li, Bingshan, Mulas, Antonella, Sidore, Carlo, Kang, Hyun M., Jackson, Anne U., Piras, Maria Grazia, Usala, Gianluca, Maninchedda, Giuseppe, Sassu, Alessandro, Serra, Fabrizio, Palmas, Maria Antonietta, Wood, William H., Njølstad, Inger, Laakso, Markku, Hveem, Kristian, Tuomilehto, Jaakko, Lakka, Timo A., Rauramaa, Rainer, Boehnke, Michael, Cucca, Francesco, Uda, Manuela, Schlessinger, David, Nagaraja, Ramaiah, Abecasis, Gonçalo R.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 01.07.2011 Public Library of Science (PLoS)
Predmet:	Biology Cholesterol Cholesterol, LDL - genetics Chromosome Mapping Estimates European Continental Ancestry Group - genetics Genetic Loci - genetics Genetic Predisposition to Disease Genetic Variation Genetics Genome-Wide Association Study Genomes Humans Italy Low density lipoprotein Low density lipoproteins Physiological aspects Polymorphism, Single Nucleotide - genetics Volunteers Italy United States
ISSN:	1553-7404, 1553-7390, 1553-7404
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors also contributed equally to this work. Conceived and designed the experiments: SS GRA DS. Performed the experiments: AM WHW RN GU. Analyzed the data: SS BL CS AUJ. Contributed reagents/materials/analysis tools: MU DS GRA. Wrote the paper: SS GRA. Contributed to genotyping chip design: BL HMK GRA. Collected phenotypes: MGP. Provided replication samples: GM AS FS MAP IN ML KH JT MB TAL RR. Provided critical revisions: BL AM FC MU DS RN MB.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1002198