TY - JOUR
T1 - Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
AU - Asselbergs, Folkert W.
AU - Guo, Yiran
AU - van Iperen, Erik P. A.
AU - Sivapalaratnam, Suthesh
AU - Tragante, Vinicius
AU - Lanktree, Matthew B.
AU - Lange, Leslie A.
AU - Almoguera, Berta
AU - Appelman, Yolande E.
AU - Barnard, John
AU - Baumert, Jens
AU - Beitelshees, Amber L.
AU - Bhangale, Tushar R.
AU - Chen, Yii-Der Ida
AU - Gaunt, Tom R.
AU - Gong, Yan
AU - Hopewell, Jemma C.
AU - Johnson, Toby
AU - Kleber, Marcus E.
AU - Langaee, Taimour Y.
AU - Li, Mingyao
AU - Li, Yun R.
AU - Liu, Kiang
AU - McDonough, Caitrin W.
AU - Meijs, Matthijs El.
AU - Middelberg, Rita P. S.
AU - Musunuru, Kiran
AU - Nelson, Christopher P.
AU - O'Connell, Jeffery R.
AU - Padmanabhan, Sandosh
AU - Pankow, James S.
AU - Pankratz, Nathan
AU - Rafelt, Suzanne
AU - Rajagopalan, Ramakrishnan
AU - Romaine, Simon P. R.
AU - Schork, Nicholas J.
AU - Shaffer, Jonathan
AU - Shen, Haiqing
AU - Smith, Erin N.
AU - Tischfield, Sam E.
AU - van der Most, Peter J.
AU - van Vliet-Ostaptchouk, Jana V.
AU - Verweij, Niek
AU - Volcik, Kelly A.
AU - Zhang, Li
AU - Bailey, Kent R.
AU - Bailey, Kristian M.
AU - Bauer, Florianne
AU - Boer, Jolanda M. A.
AU - Connell, John M.
AU - LifeLines Cohort Study
PY - 2012/11/2
Y1 - 2012/11/2
N2 - 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.
AB - 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.
KW - COMPLEX TRAITS
KW - DENSITY-LIPOPROTEIN CHOLESTEROL
KW - GENOME-WIDE ASSOCIATION
KW - PLASMA TRIGLYCERIDES
KW - FAMILIAL HYPERCHOLESTEROLEMIA
KW - MISSING HERITABILITY
KW - QUANTITATIVE TRAITS
KW - STATISTICAL-MODEL
KW - APOLIPOPROTEIN B-100
KW - CORONARY-HEART-DISEASE
U2 - 10.1016/j.ajhg.2012.08.032
DO - 10.1016/j.ajhg.2012.08.032
M3 - Article
SN - 0002-9297
VL - 91
SP - 823
EP - 838
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -