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

Folkert W. Asselbergs, Yiran Guo, Erik P.A. Van Iperen, Suthesh Sivapalaratnam, Vinicius Tragante, Matthew B. Lanktree, Leslie A. Lange, Berta Almoguera, Yolande E. Appelman, John Barnard, Jens Baumert, Amber L. Beitelshees, Tushar R. Bhangale, Yii Der Ida Chen, Tom R. Gaunt, Yan Gong, Jemma C. Hopewell, Toby Johnson, Marcus E. Kleber, Taimour Y. LangaeeMingyao Li, Yun R. Li, Kiang Liu, Caitrin W. McDonough, Matthijs F.L. Meijs, Rita P.S. Middelberg, Kiran Musunuru, Christopher P. Nelson, Jeffery R. O'Connell, Sandosh Padmanabhan, James S. Pankow, Nathan Pankratz, Suzanne Rafelt, Ramakrishnan Rajagopalan, Simon P.R. Romaine, Nicholas J. Schork, Jonathan Shaffer, Haiqing Shen, Erin N. Smith, Sam E. Tischfield, Peter J. Van Der Most, Jana V. Van Vliet-Ostaptchouk, Niek Verweij, Kelly A. Volcik, Li Zhang, Kent R. Bailey, Kristian M. Bailey, Florianne Bauer, Jolanda M.A. Boer, Peter S. Braund, Amber Burt, Paul R. Burton, Sarah G. Buxbaum, Wei Chen, Rhonda M. Cooper-Dehoff, L. Adrienne Cupples, Jonas S. Dejong, Christian Delles, David Duggan, Myriam Fornage, Clement E. Furlong, Nicole Glazer, John G. Gums, Claire Hastie, Michael V. Holmes, Thomas Illig, Susan A. Kirkland, Mika Kivimaki, Ronald Klein, Barbara E. Klein, Charles Kooperberg, Kandice Kottke-Marchant, Meena Kumari, Andrea Z. Lacroix, Laya Mallela, Gurunathan Murugesan, Jose Ordovas, Willem H. Ouwehand, Wendy S. Post, Richa Saxena, Hubert Scharnagl, Pamela J. Schreiner, Tina Shah, Denis C. Shields, Daichi Shimbo, Sathanur R. Srinivasan, Ronald P. Stolk, Daniel I. Swerdlow, Herman A. Taylor, Eric J. Topol, Elina Toskala, Joost L. Van Pelt, Jessica Van Setten, Salim Yusuf, John C. Whittaker, A. H. Zwinderman, Sonia S. Anand, Anthony J. Balmforth, Gerald S. Berenson, Connie R. Bezzina, Bernhard O. Boehm, Eric Boerwinkle, Juan P. Casas, Mark J. Caulfield, Robert Clarke, John M. Connell, Karen J. Cruickshanks, Karina W. Davidson, Ian N.M. Day, Paul I.W. De Bakker, Pieter A. Doevendans, Anna F. Dominiczak, Alistair S. Hall, Catharina A. Hartman, Christian Hengstenberg, Hans L. Hillege, Marten H. Hofker, Steve E. Humphries, Gail P. Jarvik, Julie A. Johnson, Bernhard M. Kaess, Sekar Kathiresan, Wolfgang Koenig, Debbie A. Lawlor, Winfried März, Olle Melander, Braxton D. Mitchell, Grant W. Montgomery, Patricia B. Munroe, Sarah S. Murray, Stephen J. Newhouse, N. Charlotte Onland-Moret, Neil Poulter, Bruce Psaty, Susan Redline, Stephen S. Rich, Jerome I. Rotter, Heribert Schunkert, Peter Sever, Alan R. Shuldiner, Roy L. Silverstein, Alice Stanton, Barbara Thorand, Mieke D. Trip, Michael Y. Tsai, Pim Van Der Harst, Ellen Van Der Schoot, Yvonne T. Van Der Schouw, W. M.Monique Verschuren, Hugh Watkins, Arthur A.M. Wilde, Bruce H.R. Wolffenbuttel, John B. Whitfield, G. Kees Hovingh, Christie M. Ballantyne, Cisca Wijmenga, Muredach P. Reilly, Nicholas G. Martin, James G. Wilson, Daniel J. Rader, Nilesh J. Samani, Alex P. Reiner, Robert A. Hegele, John J.P. Kastelein, Aroon D. Hingorani, Philippa J. Talmud, Hakon Hakonarson, Clara C. Elbers, Brendan J. Keating, Fotios Drenos

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)823-838
Number of pages16
JournalAmerican journal of human genetics
Volume91
Issue number5
DOIs
StatePublished - Nov 2 2012

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Asselbergs, F. W., Guo, Y., Van Iperen, E. P. A., 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. D. I., Gaunt, T. R., Gong, Y., Hopewell, J. C., Johnson, T., Kleber, M. E., ... Drenos, F. (2012). Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci. American journal of human genetics, 91(5), 823-838. https://doi.org/10.1016/j.ajhg.2012.08.032