Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
Creators: name: Asselbergs, Folkert W.
name: Guo, Yiran
name: Van Iperen, Erik P. A.
name: Sivapalaratnam, Suthesh
name: Tragante, Vinicius
name: Lanktree, Matthew B.
name: Lange, Leslie A.
name: Almoguera, Berta
name: Appelman, Yolande E.
name: Barnard, John
name: Baumert, Jens
name: Beitelshees, Amber L.
name: Bhangale, Tushar R.
name: Chen, Yii-Der Ida
name: Gaunt, Tom R.
name: Gong, Yan
name: Hopewell, Jemma C.
name: Johnson, Toby
name: Kleber, Marcus E.
name: Langaee, Taimour Y.
name: Li, Mingyao
name: Li, Yun R.
name: Liu, Kiang
name: McDonough, Caitrin W.
name: Meijs, Matthijs F. L.
name: Middelberg, Rita P. S.
name: Musunuru, Kiran
name: Nelson, Christopher P.
name: O’Connell, Jeffrey R.
name: Padmanabhan, Sandosh
name: Pankow, James S.
name: Pankratz, Nathan
name: Rafelt, Suzanne
name: Rajagopalan, Ramakrishnan
name: Romaine, Simon P. R.
name: Schork, Nicholas J.
name: Shaffer, Jonathan
name: Shen, Haiqing
name: Smith, Erin N.
name: Tischfield, Sam E.
name: Van Der Most, Peter J.
name: Van Vliet-Ostaptchouk, Jana V.
name: Verweij, Niek
name: Volcik, Kelly A.
name: Zhang, Li
name: Bailey, Kent R.
name: Bailey, Kristian M.
name: Bauer, Florianne
name: Boer, Jolanda M. A.
name: Braund, Peter S.
name: Burt, Amber
name: Burton, Paul R.
name: Buxbaum, Sarah G.
name: Chen, Wei
name: Cooper-DeHoff, Rhonda M.
name: Cupples, L. Adrienne
name: DeJong, Jonas S.
name: Delles, Christian
name: Duggan, David
name: Fornage, Myriam
name: Furlong, Clement E.
name: Glazer, Nicole
name: Gums, John G.
name: Hastie, Claire
name: Holmes, Michael V.
name: Illig, Thomas
name: Kirkland, Susan A.
name: Kivimaki, Mika
name: Klein, Ronald
name: Klein, Barbara E.
name: Kooperberg, Charles
name: Kottke-Marchant, Kandice
name: Kumari, Meena
name: LaCroix, Andrea Z.
name: Mallela, Laya
name: Murugesan, Gurunathan
name: Ordovas, Jose
name: Ouwehand, Willem H.
name: Post, Wendy S.
name: Saxena, Richa
name: Scharnagl, Hubert
name: Schreiner, Pamela J.
name: Shah, Tina
name: Shields, Denis C.
name: Shimbo, Daichi
name: Srinivasan, Sathanur R.
name: Stolk, Ronald P.
name: Swerdlow, Daniel I.
name: Taylor Jr., Herman A.
name: Topol, Eric J.
name: Toskala, Elina
name: Van Pelt, Joost L.
name: Van Setten, Jessica
name: Yusuf, Salim
name: Whittaker, John C.
name: Zwinderman, A. H.
name: Anand, Sonia S.
name: Balmforth, Anthony J.
name: Berenson, Gerald S.
name: Bezzina, Connie R.
name: Boehm, Bernhard O.
name: Boerwinkle, Eric
name: Casas, Juan P.
name: Caulfield, Mark J.
name: Clarke, Robert
name: Connell, John M.
name: Cruickshanks, Karen J.
name: Davidson, Karina W.
name: Day, Ian N. M.
name: De Bakker, Paul I. W.
name: Doevendans, Pieter A.
name: Dominiczak, Anna F.
name: Hall, Alistair S.
name: Hartman, Catharina A.
name: Hengstenberg, Christian
name: Hillege, Hans L.
name: Hofker, Marten H.
name: Humphries, Steve E.
name: Jarvik, Gail P.
name: Johnson, Julie A.
name: Kaess, Bernhard M.
name: Kathiresan, Sekar
name: Koenig, Wolfgang
name: Lawlor, Debbie A.
name: Marz, Winfried
name: Melander, Olle
name: Mitchell, Braxton D.
name: Montgomery, Grant W.
name: Munroe, Patricia B.
name: Murray, Sarah S.
name: Newhouse, Stephen J.
name: Onland-Moret, N. Charlotte
name: Poulter, Neil
name: Psaty, Bruce
name: Redline, Susan
name: Rich, Stephen S.
name: Rotter, Jerome I.
name: Schunkert, Heribert
name: Sever, Peter
name: Shuldiner, Alan R.
name: Silverstein, Roy L.
name: Stanton, Alice
name: Thorand, Barbara
name: Trip, Mieke D.
name: Tsai, Michael Y.
name: Van Der Harst, Pim
name: Van Der Schoot, Ellen
name: Van Der Schouw, Yvonne T.
name: Verschuren, W. M. Monique
name: Watkins, Hugh
name: Wilde, Arthur A. M.
name: Wolffenbuttel, Bruce H. R.
name: Whitfield, John B.
name: Hovingh, G. Kees
name: Ballantyne, Christie M.
name: Wijmenga, Cisca
name: Reilly, Muredach P.
name: Martin, Nicholas G.
name: LifeLines Cohort Study
Publisher: name: Columbia University
Year: 2012
Subjects: subject: Single nucleotide polymorphisms
subject: Lipids
subject: Meta-analysis
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular biology
subject: Medical sciences

description: 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.