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Title: Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci

Author
item ASSELBERGS, FOLKERT - University Medical Center - Utrecht
item GUO, YIRAN - The Children'S Hospital Of Philadelphia
item VAN IPEREN, ERIK - University Of Amsterdam
item SIVAPALARATNAM, SUTHESH - University Of Amsterdam
item TRAGANTE, VINCENT - University Medical Center - Utrecht
item LANKTREE, MATTHEW - University Of Western Ontario
item LANGE, LESLIE - University Of North Carolina
item ALMOGUERA, BERTA - The Children'S Hospital Of Philadelphia
item APPELMAN, YOLANDE - Vu University Medical Center
item BARNARD, JOHN - Cleveland Clinic
item BAUMERT, JENS - German Research Center For Environmental Health
item BEITELSHEES, AMBER - University Of Maryland
item BHANGALE, TUSHAR - Genentech
item CHEN, YII-DER IDA - Cedars-Sinai Medical Center
item GAUNT, TOM - University Of Bristol
item GONG, YAN - University Of Florida
item HOPEWELL, JEMMA - University Of Oxford
item JOHNSON, TOBY - Queen Mary University Of London
item KLEBER, MARCUS - University Of Heidelberg
item LANGAEE, TAIMOUR - University Of Florida
item LI, MINGYAO - University Of Pennsylvania
item LI, YUN - The Children'S Hospital Of Philadelphia
item LIU, KLANG - Northwestern University
item MCDONOUGH, CAITRIN - University Of Florida
item MEIJS, MATTHIJS - University Medical Center Utrecht
item MIDDELBERG, RITA - Royale Brisbane Hospital
item MUSUNURU, KIRAN - Massachusetts Institute Of Technology
item NELSON, CHRISTOPHER - University Of Leicester
item O'CONNELL, JEFFREY - University Of Maryland
item PADMANABHAN, SANDOSH - University Of Glasgow
item PANKOW, JAMES - University Of Minnesota
item PANKRATZ, NATHAN - University Of Minnesota
item RAFELT, SUZANNE - University Of Leicester
item RAJAGOPALAN, RAMAKRISHNAN - University Of Washington
item ROMAINE, SIMON - University Of Leeds
item SCHORK, NICHOLAS - Scripps Institute
item SHAFFER, JONATHAN - Columbia University
item SHEN, HAIQING - University Of Maryland
item SMIN, ERIN - University Of California
item TISCHFIELD, SAM - Cornell University
item VAN DER MOST, PETER - University Of Groningen
item VANVLIET-OSTAPTCHOUK, JANA - University Of Groningen
item VERWEIJ, NICK - University Of Groningen
item VOLCIK, KELLY - University Of Texas
item ZHANG, LI - Cleveland Clinic
item BAILEY, KENT - Mayo Clinic
item BAILEY, KRISTIAN - University Of Leeds
item BAUER, FLORIANNE - University Medical Center Utrecht
item BOER, JOLANDA - National Institute For Public Health And The Environment (RIVM)
item BRAUND, PETER - University Of Leicester
item BURT, AMBER - University Of Washington
item BURTON, PAUL - University Of Leicester
item BUXBAUM, SARAH - Jackson State University
item CHEN, WEI - Tulane University
item COOPER-DEHOFF, RHONDA - University Of Florida
item CUPPLES, L ANDRIANNE - Boston University
item DEJONG, JONAS - University Of Amsterdam
item DELLES, CHRISTIAN - University Of Glasgow
item DUGGAN, DAVID - University Of Texas
item FORNAGE, MYRIAM - University Of Texas
item FURLONG, CLEMENT - University Of Washington
item GLAZER, NICOLE - Boston University
item GUMS, JOHN - University Of Florida
item HASTIE, CLAIRE - University Of Glasgow
item HOLMES, MICHAEL - University College London
item ILLIG, THOMAS - German Research Center For Environmental Health
item KIRKLAND, SUSAN - Dalhousie University
item KIVIMAKI, MIKA - University College London
item KLEIN, RONALD - University Of Wisconsin
item KLEIN, BARBARA - University Of Wisconsin
item KOOPERBERG, CHARLES - Fred Hutchinson Cancer Research Center
item KOTTKE-MARCHANT, KANDICE - Cleveland Clinic
item KUMARI, MEENA - University College London
item LACROIX, ANDREA - Fred Hutchinson Cancer Research Center
item MALLELA, LAYA - The Children'S Hospital Of Philadelphia
item MURUGESAN, GURUNATHAN - Cleveland Clinic
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item OUWEHAND, WILLEM - University Of Cambridge
item POST, WENDY - Johns Hopkins University
item SAXENA, RICHA - Massachusetts General Hospital
item SCHARNAGL, HUBERT - Medical University Of Graz
item SCHREINER, PAMELA - University Of Minnesota
item SHAH, TINA - University College London
item SHIELDS, DENIS - University College Dublin

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.