TY - JOUR
T1 - Genetic architecture of circulating lipid levels
AU - Demirkan, Ayse
AU - Amin, Najaf
AU - Isaacs, Aaron
AU - Jarvelin, Marjo-Riitta
AU - Whitfield, John B
AU - Wichmann, Heinz-Erich
AU - Kyvik, Kirsten O H M
AU - Rudan, Igor
AU - Gieger, Christian
AU - Hicks, Andrew A
AU - Johansson, Åsa
AU - Hottenga, Jouke-Jan
AU - Smith, Johannes J
AU - Wild, Sarah H
AU - Pedersen, Nancy L
AU - Willemsen, Gonneke
AU - Mangino, Massimo
AU - Hayward, Caroline
AU - Uitterlinden, André G
AU - Hofman, Albert
AU - Witteman, Jacqueline
AU - Montgomery, Grant W
AU - Pietiläinen, Kirsi H
AU - Rantanen, Taina
AU - Kaprio, Jaakko
AU - Döring, Angela
AU - Pramstaller, Peter P
AU - Gyllensten, Ulf
AU - de Geus, Eco J C
AU - Penninx, Brenda W
AU - Wilson, James F
AU - Rivadeneria, Fernando
AU - Magnusson, Patrik K E
AU - Boomsma, Dorret I
AU - Spector, Tim
AU - Campbell, Harry
AU - Hoehne, Birgit
AU - Martin, Nicholas G
AU - Oostra, Ben A
AU - McCarthy, Mark
AU - Peltonen-Palotie, Leena
AU - Aulchenko, Yurii
AU - Visscher, Peter M
AU - Ripatti, Samuli
AU - Janssens, A Cecile J W
AU - van Duijn, Cornelia M
AU - ENGAGE Consortium
PY - 2011/7
Y1 - 2011/7
N2 - 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.
AB - 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.
KW - Female
KW - Genome-Wide Association Study
KW - Humans
KW - Lipid Metabolism/genetics
KW - Lipids/blood
KW - Male
KW - Metabolic Networks and Pathways/genetics
KW - Models, Genetic
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Quantitative Trait Loci/genetics
KW - Risk
U2 - 10.1038/ejhg.2011.21
DO - 10.1038/ejhg.2011.21
M3 - Article
C2 - 21448234
SN - 1018-4813
VL - 19
SP - 813
EP - 819
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -