Advanced

Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

Asselbergs, Folkert W.; Guo, Yiran; van Iperen, Erik P. A.; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B.; Lange, Leslie A.; Almoguera, Berta; Appelman, Yolande E. and Barnard, John, et al. (2012) In American Journal of Human Genetics 91(5). p.823-838
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 similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 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... (More)
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 similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 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. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
American Journal of Human Genetics
volume
91
issue
5
pages
823 - 838
publisher
Cell Press
external identifiers
  • wos:000311011400005
  • scopus:84868470681
ISSN
0002-9297
DOI
10.1016/j.ajhg.2012.08.032
language
English
LU publication?
yes
id
19739b80-cdd4-4db7-b175-028cfda89d8f (old id 3244000)
date added to LUP
2013-01-07 09:34:57
date last changed
2017-11-12 03:10:54
@article{19739b80-cdd4-4db7-b175-028cfda89d8f,
  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 similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 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.},
  author       = {Asselbergs, Folkert W. and Guo, Yiran and van Iperen, Erik P. A. and Sivapalaratnam, Suthesh and Tragante, Vinicius and Lanktree, Matthew B. and Lange, Leslie A. and Almoguera, Berta and Appelman, Yolande E. and Barnard, John and Baumert, Jens and Beitelshees, Amber L. and Bhangale, Tushar R. and Chen, Yii-Der Ida and Gaunt, Tom R. and Gong, Yan and Hopewell, Jemma C. and Johnson, Toby and Kleber, Marcus E. and Langaee, Taimour Y. and Li, Mingyao and Li, Yun R. and Liu, Kiang and McDonough, Caitrin W. and Meijs, Matthijs El. and Middelberg, Rita P. S. and Musunuru, Kiran and Nelson, Christopher P. and O'Connell, Jeffery R. and Padmanabhan, Sandosh and Pankow, James S. and Pankratz, Nathan and Rafelt, Suzanne and Rajagopalan, Ramakrishnan and Romaine, Simon P. R. and Schork, Nicholas J. and Shaffer, Jonathan and Shen, Haiqing and Smith, Erin N. and Tischfield, Sam E. and van der Most, Peter J. and van Vliet-Ostaptchouk, Jana V. and Verweij, Niek and Volcik, Kelly A. and Zhang, Li and Bailey, Kent R. and Bailey, Kristian M. and Bauer, Florianne and Boer, Jolanda M. A. and Braund, Peter S. and Burt, Amber and Burton, Paul R. and Buxbaum, Sarah G. and Chen, Wei and Cooper-DeHoff, Rhonda M. and Cupples, L. Adrienne and deJong, Jonas S. and Delles, Christian and Duggan, David and Fornage, Myriam and Furlong, Clement E. and Glazer, Nicole and Gums, John G. and Hastie, Claire and Holmes, Michael V. and Illig, Thomas and Kirkland, Susan A. and Kivimaki, Mika and Klein, Ronald and Klein, Barbara E. and Kooperberg, Charles and Kottke-Marchant, Kandice and Kumari, Meena and LaCroix, Andrea Z. and Mallela, Laya and Murugesan, Gurunathan and Ordovas, Jose and Ouwehand, Willem H. and Post, Wendy S. and Saxena, Richa and Scharnagl, Hubert and Schreiner, Pamela J. and Shah, Tina and Shields, Denis C. and Shimbo, Daichi and Srinivasan, Sathanur R. and Stolk, Ronald P. and Swerdlow, Daniel I. and Taylor Jr, Herman A. and Topo, Eric J. and Toskala, Elina and van Pelt, Joost L. and van Setten, Jessica and Yusuf, Salim and Whittaker, John C. and Zwinderman, A. H. and Anand, Sonia S. and Balmforth, Anthony J. and Berenson, Gerald S. and Bezzina, Connie R. and Boehm, Bernhard O. and Boerwinkle, Eric and Casas, Juan P. and Caulfield, Mark J. and Clarke, Robert and Connell, John M. and Cruickshanks, Karen J. and Davidson, Karina W. and Day, Ian N. M. and de Bakker, Paul I. W. and Doevendans, Pieter A. and Dominiczak, Anna E. and Hall, Alistair S. and Hartman, Catharina A. and Hengstenberg, Christian and Hillege, Hans L. and Hofker, Marten H. and Humphries, Steve E. and Jarvik, Gail P. and Johnson, Julie A. and Kaess, Bernhard M. and Kathiresan, Sekar and Koenig, Wolfgang and Lawlor, Debbie A. and Maerz, Winfried and Melander, Olle and Mitchell, Braxton D. and Montgomery, Grant W. and Munroe, Patricia B. and Murray, Sarah S. and Newhouse, Stephen J. and Onland-Moret, N. Charlotte and Poulter, Neil and Psaty, Bruce and Redline, Susan and Rich, Stephen S. and Rotter, Jerome I. and Schunkert, Heribert and Sever, Peter and Shuldiner, Alan R. and Silverstein, Roy L. and Stanton, Alice and Thorand, Barbara and Trip, Mieke D. and Tsai, Michael Y. and van der Harst, Pim and van der Schoot, Ellen and van der Schouw, Yvonne T. and Verschuren, W. M. Monique and Watkins, Hugh and Wilde, Arthur A. M. and Wolffenbuttel, Bruce H. R. and Whitfield, John B. and Hovingh, G. Kees and Ballantyne, Christie M. and Wijmenga, Cisca and Reilly, Muredach P. and Martin, Nicholas G. and Wilson, James G. and Rader, Daniel J. and Samani, Nilesh J. and Reiner, Alex P. and Hegele, Robert A. and Kastelein, John J. P. and Hingorani, Aroon D. and Talmud, Philippa J. and Hakonarson, Hakon and Elbers, Clara C. and Keating, Brendan J. and Drenos, Fotios},
  issn         = {0002-9297},
  language     = {eng},
  number       = {5},
  pages        = {823--838},
  publisher    = {Cell Press},
  series       = {American Journal of Human Genetics},
  title        = {Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2012.08.032},
  volume       = {91},
  year         = {2012},
}