title: Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability.
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.
authors.affiliation: Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato, Italy. serena.sanna@inn.cnr.it
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Bingshan
authors.initials: B
authors.lastname: Li
authors.forename: Antonella
authors.initials: A
authors.lastname: Mulas
authors.forename: Carlo
authors.initials: C
authors.lastname: Sidore
authors.forename: Hyun M
authors.initials: HM
authors.lastname: Kang
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Piras
authors.forename: Gianluca
authors.initials: G
authors.lastname: Usala
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Maninchedda
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sassu
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Serra
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Palmas
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.forename: Inger
authors.initials: I
authors.lastname: Njølstad
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Kristian
authors.initials: K
authors.lastname: Hveem
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.forename: Timo A
authors.initials: TA
authors.lastname: Lakka
authors.forename: Rainer
authors.initials: R
authors.lastname: Rauramaa
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Francesco
authors.initials: F
authors.lastname: Cucca
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Nagaraja
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
mesh_terms: D008078:Cholesterol, LDL / Q000235:genetics*; D002874:Chromosome Mapping; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007558:Italy; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL