Genetic architecture of circulating lipid levels

Ayşe 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 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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

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.
OriginalsprogEngelsk
TidsskriftEuropean Journal of Human Genetics
Vol/bind19
Udgave nummer7
Sider (fra-til)813-9
Antal sider7
ISSN1018-4813
DOI
StatusUdgivet - 1. jul. 2011

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