Genetic architecture of circulating lipid levels

Ayse Demirkan, Najaf Amin, Aaron Isaacs, Marjo-Riitta Jarvelin, John B Whitfield, Heinz-Erich Wichmann, Kirsten O H M Kyvik, Igor Rudan, Christian Gieger, Andrew A Hicks, Åsa Johansson, Jouke-Jan Hottenga, Johannes J Smith, Sarah H Wild, Nancy L Pedersen, Gonneke Willemsen, Massimo Mangino, Caroline Hayward, André G Uitterlinden, Albert HofmanJacqueline Witteman, Grant W Montgomery, Kirsi H Pietiläinen, Taina Rantanen, Jaakko Kaprio, Angela Döring, Peter P Pramstaller, Ulf Gyllensten, Eco J C de Geus, Brenda W Penninx, James F Wilson, Fernando Rivadeneria, Patrik K E Magnusson, Dorret I Boomsma, Tim Spector, Harry Campbell, Birgit Hoehne, Nicholas G Martin, Ben A Oostra, Mark McCarthy, Leena Peltonen-Palotie, Yurii Aulchenko, Peter M Visscher, Samuli Ripatti, A Cecile J W Janssens, Cornelia M van Duijn*, ENGAGE Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)813-9
Number of pages7
JournalEuropean Journal of Human Genetics
Issue number7
Publication statusPublished - Jul 2011
Externally publishedYes


  • Female
  • Genome-Wide Association Study
  • Humans
  • Lipid Metabolism/genetics
  • Lipids/blood
  • Male
  • Metabolic Networks and Pathways/genetics
  • Models, Genetic
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci/genetics
  • Risk

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