title: Genetic architecture of circulating lipid levels.
abstract: Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
authors: Genetic Epidemiology Unit, Department of Epidemiology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Ayşe
authors: A
authors: Demirkan
authors: Najaf
authors: N
authors: Amin
authors: Aaron
authors: A
authors: Isaacs
authors: Marjo-Riitta
authors: MR
authors: Jarvelin
authors: John B
authors: JB
authors: Whitfield
authors: Heinz-Erich
authors: HE
authors: Wichmann
authors: Kirsten O H M
authors: KO
authors: Kyvik
authors: Igor
authors: I
authors: Rudan
authors: Christian
authors: C
authors: Gieger
authors: Andrew A
authors: AA
authors: Hicks
authors: Åsa
authors: Å
authors: Johansson
authors: Jouke-Jan
authors: JJ
authors: Hottenga
authors: Johannes J
authors: JJ
authors: Smith
authors: Sarah H
authors: SH
authors: Wild
authors: Nancy L
authors: NL
authors: Pedersen
authors: Gonneke
authors: G
authors: Willemsen
authors: Massimo
authors: M
authors: Mangino
authors: Caroline
authors: C
authors: Hayward
authors: André G
authors: AG
authors: Uitterlinden
authors: Albert
authors: A
authors: Hofman
authors: Jacqueline
authors: J
authors: Witteman
authors: Grant W
authors: GW
authors: Montgomery
authors: Kirsi H
authors: KH
authors: Pietiläinen
authors: Taina
authors: T
authors: Rantanen
authors: Jaakko
authors: J
authors: Kaprio
authors: Angela
authors: A
authors: Döring
authors: Peter P
authors: PP
authors: Pramstaller
authors: Ulf
authors: U
authors: Gyllensten
authors: Eco J C
authors: EJ
authors: de Geus
authors: Brenda W
authors: BW
authors: Penninx
authors: James F
authors: JF
authors: Wilson
authors: Fernando
authors: F
authors: Rivadeneria
authors: Patrik K E
authors: PK
authors: Magnusson
authors: Dorret I
authors: DI
authors: Boomsma
authors: Tim
authors: T
authors: Spector
authors: Harry
authors: H
authors: Campbell
authors: Birgit
authors: B
authors: Hoehne
authors: Nicholas G
authors: NG
authors: Martin
authors: Ben A
authors: BA
authors: Oostra
authors: Mark
authors: M
authors: McCarthy
authors: Leena
authors: L
authors: Peltonen-Palotie
authors: Yurii
authors: Y
authors: Aulchenko
authors: Peter M
authors: PM
authors: Visscher
authors: Samuli
authors: S
authors: Ripatti
authors: A Cecile J W
authors: AC
authors: Janssens
authors: Cornelia M
authors: CM
authors: van Duijn
mesh_terms: D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008055:Lipids / Q000097:blood* / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D012306:Risk
chemical_list: D008055:Lipids