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. 2009 Jan;41(1):47-55.
doi: 10.1038/ng.269. Epub 2008 Dec 7.

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Yurii S Aulchenko  1 , Samuli Ripatti, Ida Lindqvist, Dorret Boomsma, Iris M Heid, Peter P Pramstaller, Brenda W J H Penninx, A Cecile J W Janssens, James F Wilson, Tim Spector, Nicholas G Martin, Nancy L Pedersen, Kirsten Ohm Kyvik, Jaakko Kaprio, Albert Hofman, Nelson B Freimer, Marjo-Riitta Jarvelin, Ulf Gyllensten, Harry Campbell, Igor Rudan, Asa Johansson, Fabio Marroni, Caroline Hayward, Veronique Vitart, Inger Jonasson, Cristian Pattaro, Alan Wright, Nick Hastie, Irene Pichler, Andrew A Hicks, Mario Falchi, Gonneke Willemsen, Jouke-Jan Hottenga, Eco J C de Geus, Grant W Montgomery, John Whitfield, Patrik Magnusson, Juha Saharinen, Markus Perola, Kaisa Silander, Aaron Isaacs, Eric J G Sijbrands, Andre G Uitterlinden, Jacqueline C M Witteman, Ben A Oostra, Paul Elliott, Aimo Ruokonen, Chiara Sabatti, Christian Gieger, Thomas Meitinger, Florian Kronenberg, Angela Döring, H-Erich Wichmann, Johannes H Smit, Mark I McCarthy, Cornelia M van Duijn, Leena Peltonen; ENGAGE Consortium
Collaborators, Affiliations

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Yurii S Aulchenko et al. Nat Genet. 2009 Jan.

Abstract

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

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Figures

Figure 1
Figure 1
Effect of rs7395662 (MADD-FOLH1) on high-density lipoprotein separately for different cohorts and sexes.
Figure 2
Figure 2
Pathways containing an enrichment of the most strongly associated genes with total cholesterol (green circles) and their connections.
Figure 3
Figure 3
Effect of rs3846662 (HMGCR) on total cholesterol separately for different cohorts showing different effects for the two sexes.
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