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

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • 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.
  • 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 F.L.
  • Middelberg, Rita P.S.
  • Musunuru, Kiran
  • Nelson, Christopher P.
  • O’Connell, Jeffery R.
  • Padmanabhan, Sandosh
  • Pankow, James S.
  • Pankratz, Nathan
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.
Date of publication
Keyword
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • The American Journal of Human Genetics
Journal volume
  • 91
Journal issue
  • 5
Page start
  • 823
Page end
  • 838
Language
  • English
ISSN
  • 0002-9297
  • 1537-6605

Relations

Parents:

This work has no parents.

In Collection:

Items

Thumbnail Title Date Uploaded Visibility Actions
file details EuropePMC-PMC3487124.pdf November 1, 2020 Public Download