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RESEARCH PRODUCT
Genetic architecture of circulating lipid levels
Andrew A. HicksKirsi H. PietiläinenJouke-jan HottengaAyse DemirkanBrenda W.j.h. PenninxA. Cecile J.w. JanssensHeinz-erich WichmannAngela DöringSarah H. WildMark I. MccarthyMark I. MccarthyÅSa JohanssonPeter P. PramstallerPatrik K. E. MagnussonNajaf AminJames F. WilsonAndré G. UitterlindenLeena Peltonen-palotieTaina RantanenPeter M. VisscherBirgit HoehneIgor RudanJaakko KaprioAaron IsaacsDorret I. BoomsmaHarry CampbellEco J. C. De GeusJacqueline C. M. WittemanKirsten Ohm KyvikMarjo-riitta JärvelinAlbert HofmanBen A. OostraGrant W. MontgomeryTim D. SpectorYurii S. AulchenkoGonneke WillemsenCaroline HaywardMassimo ManginoNancy L. PedersenUlf GyllenstenJohn WhitfieldJohannes J SmithNicholas G. MartinFernando RivadeneriaCornelia M. Van DuijnSamuli RipattiChristian Giegersubject
Netherlands Twin Register (NTR)MaleRiskQuantitative Trait LociPopulationBlood lipidsGenome-wide association study030204 cardiovascular system & hematologyBiologyQuantitative trait locusPolymorphism Single NucleotideArticle03 medical and health sciences0302 clinical medicineLipid Metabolism/geneticsGeneticSDG 3 - Good Health and Well-beingModelsGenetic variation/dk/atira/pure/keywords/cohort_studies/netherlands_twin_register_ntr_GeneticsHumansPolymorphismeducationSerum lipids; polygenic; genome-wide association; polygenic score; pathway analysisGenetics (clinical)030304 developmental biologyGenetic associationGenetics0303 health scienceseducation.field_of_studyModels GeneticLipids/bloodMetabolic Networks and Pathways/geneticsta3141Lipid metabolismSingle Nucleotideta3142Lipid MetabolismLipidsGenetic architecture3. Good healthPhenotype/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_beingFemalelipids (amino acids peptides and proteins)Quantitative Trait Loci/geneticsMetabolic Networks and PathwaysGenome-Wide Association Studydescription
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. European Journal of Human Genetics (2011) 19, 813-819; doi:10.1038/ejhg.2011.21; published online 30 March 2011
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-07-01 | European Journal of Human Genetics |