Location: Boston, MassachusettsTitle: Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci Author
|Van Iperen, Erik|
|Chen, Yii-der Ida|
|Van Der Most, Peter|
|Cupples, L Andrianne|
Submitted to: American Society of Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/30/2012
Publication Date: 10/11/2012
Citation: Asselbergs, F.W., Guo, Y., Van Iperen, E.P., Sivapalaratnam, S., Tragante, V., Lanktree, M.B., Lange, L.A., Almoguera, B., Appelman, Y.E., Barnard, J., Baumert, J., Beitelshees, A.L., Bhangale, T.R., Chen, Y., Gaunt, T.R., Gong, Y., Hopewell, J.C., Johnson, T., Kleber, M.E., Langaee, T.Y., Li, M., Li, Y.R., Liu, K., Mcdonough, C.W., Meijs, M.F., Middelberg, R.P., Musunuru, K., Nelson, C.P., O'Connell, J.R., Padmanabhan, S., Pankow, J.S., Pankratz, N., Rafelt, S., Rajagopalan, R., Romaine, S.P., Schork, N.J., Shaffer, J., Shen, H., Smin, E.N., Tischfield, S.E., Van Der Most, P.J., Vanvliet-Ostaptchouk, J.V., Verweij, N., Volcik, K.A., Zhang, L., Bailey, K.R., Bailey, K.M., Bauer, F., Boer, J.M., Braund, P.S., Burt, A., Burton, P.R., Buxbaum, S.G., Chen, W., Cooper-Dehoff, R.M., Cupples, L., Dejong, J.S., Delles, C., Duggan, D., Fornage, M., Furlong, C.E., Glazer, N., Gums, J.G., Hastie, C., Holmes, M.V., Illig, T., Kirkland, S.A., Kivimaki, M., Klein, R., Klein, B.E., Kooperberg, C., Kottke-Marchant, K., Kumari, M., Lacroix, A.Z., Mallela, L., Murugesan, G., Ordovas, J., Ouwehand, W.H., Post, W.S., Saxena, R., Scharnagl, H., Schreiner, P.J., Shah, T., Shields, D.C., ... Drenos, F. 2012. Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. American Society of Human Genetics. 91(5):823-838. Interpretive Summary: Lipoproteins are spherical particles that carry lipids, particularly cholesterol and triglyceride, in the plasma. There is a well-established association between dyslipidemias, or disorders of lipoprotein metabolism, and coronary heart disease (CHD). Elevated levels of blood cholesterol, especially low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C) increase risk for CHD. Blood levels of these lipids are determined by both genetic and environmental factors. We recently performed a large-scale meta-analysis of genome-wide studies and identified 95 regions in the genome, which are significant predictors of blood lipid traits. In this work, we explore whether additional genes or genomic regions associated with plasma-lipid phenotypes (organism's observable characteristics or traits), could be identified by focusing on the 1% of the genome containing genes rather than the entire genome. We analyzed the data of 32 studies in 66,240 individuals of European ancestry who had information about 50,000 single-nucleotide polymorphisms (SNP - a DNA sequence variation occurring when a single molecule differs between members of a biological species or paired chromosomes in a human) covering around 2,000 genes of interest. Promising findings were replicated either in a group of individuals comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four new SNPs in established lipid genes for HDL-C, LDL-C, total cholesterol (TC), and triglycerides (TG), respectively. We also identified several lipid-related SNPs in previously unreported genes. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. In summary, this large analysis of lipid phenotypes using of a gene-centric approach identified multiple novel SNPs in established lipid genes and several previously unknown loci, suggesting that a focused genotyping approach can further increase the understanding of heritability of blood lipids and the prediction of cardiovascular risk.
Technical Abstract: Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ~50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ~2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.