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 El. 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, John M. Connell, LifeLines Cohort Study

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177 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)823-838
Number of pages16
JournalAmerican Journal of Human Genetics
Volume91
Issue number5
DOIs
Publication statusPublished - 2 Nov 2012

Keywords

  • COMPLEX TRAITS
  • DENSITY-LIPOPROTEIN CHOLESTEROL
  • GENOME-WIDE ASSOCIATION
  • PLASMA TRIGLYCERIDES
  • FAMILIAL HYPERCHOLESTEROLEMIA
  • MISSING HERITABILITY
  • QUANTITATIVE TRAITS
  • STATISTICAL-MODEL
  • APOLIPOPROTEIN B-100
  • CORONARY-HEART-DISEASE

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