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Am J Hum Genet. 2012 Nov 2;91(5):823-38. doi: 10.1016/j.ajhg.2012.08.032. Epub 2012 Oct 11.

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

Asselbergs FW1, Guo Y, van Iperen EP, Sivapalaratnam S, Tragante V, Lanktree MB, Lange LA, Almoguera B, Appelman YE, Barnard J, Baumert J, Beitelshees AL, Bhangale TR, Chen YD, Gaunt TR, Gong Y, Hopewell JC, Johnson T, Kleber ME, Langaee TY, Li M, Li YR, Liu K, McDonough CW, Meijs MF, Middelberg RP, Musunuru K, Nelson CP, O'Connell JR, Padmanabhan S, Pankow JS, Pankratz N, Rafelt S, Rajagopalan R, Romaine SP, Schork NJ, Shaffer J, Shen H, Smith EN, Tischfield SE, van der Most PJ, van Vliet-Ostaptchouk JV, Verweij N, Volcik KA, Zhang L, Bailey KR, Bailey KM, Bauer F, Boer JM, Braund PS, Burt A, Burton PR, Buxbaum SG, Chen W, Cooper-Dehoff RM, Cupples LA, deJong JS, Delles C, Duggan D, Fornage M, Furlong CE, Glazer N, Gums JG, Hastie C, Holmes MV, Illig T, Kirkland SA, Kivimaki M, Klein R, Klein BE, Kooperberg C, Kottke-Marchant K, Kumari M, LaCroix AZ, Mallela L, Murugesan G, Ordovas J, Ouwehand WH, Post WS, Saxena R, Scharnagl H, Schreiner PJ, Shah T, Shields DC, Shimbo D, Srinivasan SR, Stolk RP, Swerdlow DI, Taylor HA Jr, Topol EJ, Toskala E, van Pelt JL, van Setten J, Yusuf S, Whittaker JC, Zwinderman AH; LifeLines Cohort Study, Anand SS, Balmforth AJ, Berenson GS, Bezzina CR, Boehm BO, Boerwinkle E, Casas JP, Caulfield MJ, Clarke R, Connell JM, Cruickshanks KJ, Davidson KW, Day IN, de Bakker PI, Doevendans PA, Dominiczak AF, Hall AS, Hartman CA, Hengstenberg C, Hillege HL, Hofker MH, Humphries SE, Jarvik GP, Johnson JA, Kaess BM, Kathiresan S, Koenig W, Lawlor DA, März W, Melander O, Mitchell BD, Montgomery GW, Munroe PB, Murray SS, Newhouse SJ, Onland-Moret NC, Poulter N, Psaty B, Redline S, Rich SS, Rotter JI, Schunkert H, Sever P, Shuldiner AR, Silverstein RL, Stanton A, Thorand B, Trip MD, Tsai MY, van der Harst P, van der Schoot E, van der Schouw YT, Verschuren WM, Watkins H, Wilde AA, Wolffenbuttel BH, Whitfield JB, Hovingh GK, Ballantyne CM, Wijmenga C, Reilly MP, Martin NG, Wilson JG, Rader DJ, Samani NJ, Reiner AP, Hegele RA, Kastelein JJ, Hingorani AD, Talmud PJ, Hakonarson H, Elbers CC, Keating BJ, Drenos F.

Author information

1
Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

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.

PMID:
23063622
PMCID:
PMC3487124
DOI:
10.1016/j.ajhg.2012.08.032
[Indexed for MEDLINE]
Free PMC Article

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