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Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

TitleLarge-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.
Publication TypeJournal Article
Year of Publication2012
AuthorsAsselbergs FW, Guo Y, van Iperen EPA, et al.
Secondary AuthorsDrenos F
Corporate AuthorsLifeLines Cohort Study
JournalAm J Hum Genet
Volume91
Issue5
Pagination823-38
Date Published2012 Nov 02
ISSN1537-6605
KeywordsCholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Humans, Lipids, Male, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sex Factors, Triglycerides
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.

DOI10.1016/j.ajhg.2012.08.032
Alternate JournalAm J Hum Genet
PubMed ID23063622
PubMed Central IDPMC3487124
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
PG/07/132/24256 / / British Heart Foundation / United Kingdom
R01-HL-076784 / HL / NHLBI NIH HHS / United States
G9521010 / / Medical Research Council / United Kingdom
N01-HC-45205 / HC / NHLBI NIH HHS / United States
R01 HL088119 / HL / NHLBI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
RG/08/008/25291 / / British Heart Foundation / United Kingdom
N01-HC-05187 / HC / NHLBI NIH HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
R01 HL67406 / HL / NHLBI NIH HHS / United States
RG/07/005/23633 / / British Heart Foundation / United Kingdom
N01-HC-48047 / HC / NHLBI NIH HHS / United States
U01 HL72515 / HL / NHLBI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
U01 GM074492 / GM / NIGMS NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
R01 AG011099 / AG / NIA NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
R37 AG011099 / AG / NIA NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
G9521010D / / Medical Research Council / United Kingdom
AG13196 / AG / NIA NIH HHS / United States
N01-HC-45204 / HC / NHLBI NIH HHS / United States
R01 AG021917 / AG / NIA NIH HHS / United States
N01-HC-95159 / HC / NHLBI NIH HHS / United States
R01 AG18728 / AG / NIA NIH HHS / United States
UL1 RR025774 / RR / NCRR NIH HHS / United States
U01-HL-080295 / HL / NHLBI NIH HHS / United States
/ / Department of Health / United Kingdom
RG/2001004 / / British Heart Foundation / United Kingdom
N01-HC-95095 / HC / NHLBI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
R01 AG016592 / AG / NIA NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
MC_U137686857 / / Medical Research Council / United Kingdom
R01-AG-028321 / AG / NIA NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01-HC-15103 / HC / NHLBI NIH HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P01 HL088117 / HL / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
/ / Intramural NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01-HC-45134 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
P20 MD006899 / MD / NIMHD NIH HHS / United States
HL36310 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
PG/07/131/24254 / / British Heart Foundation / United Kingdom
U01-GM074492 / GM / NIGMS NIH HHS / United States
N01-HC-55222 / HC / NHLBI NIH HHS / United States
R01-HL-071205 / HL / NHLBI NIH HHS / United States
SP/08/005/25115 / / British Heart Foundation / United Kingdom
N01-HC-48049 / HC / NHLBI NIH HHS / United States
K24 HL084034 / HL / NHLBI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
UL1 TR000064 / TR / NCATS NIH HHS / United States
N01-HC-95160 / HC / NHLBI NIH HHS / United States
R01 HL091099 / HL / NHLBI NIH HHS / United States
RG/08/008 / / British Heart Foundation / United Kingdom
PG/02/128 / / British Heart Foundation / United Kingdom
HD-062783 / HD / NICHD NIH HHS / United States
G0802432 / / Medical Research Council / United Kingdom
CH/98001 / / British Heart Foundation / United Kingdom
SP/07/007/23671 / / British Heart Foundation / United Kingdom
U10EY06594 / EY / NEI NIH HHS / United States
R37AG11099 / AG / NIA NIH HHS / United States
AG-16592 / AG / NIA NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
N01-HC-95161 / HC / NHLBI NIH HHS / United States
PG/07/133/24260 / / British Heart Foundation / United Kingdom
CH/03/001 / / British Heart Foundation / United Kingdom
N01-HC-95100 / HC / NHLBI NIH HHS / United States
HS06516 / HS / AHRQ HHS / United States
N01-HC-48048 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
HD-061437 / HD / NICHD NIH HHS / United States
R01-HL-092577 / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
N01-HC-85084 / HC / NHLBI NIH HHS / United States
P50HL81011 / HL / NHLBI NIH HHS / United States
R01AG021917 / AG / NIA NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
RG/10/12/28456 / / British Heart Foundation / United Kingdom