Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci Academic Article uri icon

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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.

authors

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

publication date

  • November 2012