학술논문
Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
Document Type
article
Author
Asselbergs, Folkert W; Guo, Yiran; van Iperen, Erik PA; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B; 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; Study, LifeLines Cohort; Anand, Sonia S; Balmforth, Anthony J; Berenson, Gerald S
Source
American Journal of Human Genetics. 91(5)
Subject
Language
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.