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 Langaee; Mingyao Li; Yun R Li; Kiang Liu; Caitrin W McDonough; Matthijs F L 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; Mika Kivimaki; Ian N M Day; Debbie A Lawlor; Fotios Drenos; LifeLines Cohort Study

doi:10.1016/j.ajhg.2012.08.032

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 F L 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, Mika Kivimaki, Ian N M Day, Debbie A Lawlor, Fotios Drenos, LifeLines Cohort Study

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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.

Original language	English
Pages (from-to)	823-838
Journal	American Journal of Human Genetics
Volume	91
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2012.08.032
Publication status	Published - 2 Nov 2012

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Asselbergs, F. W., Guo, Y., van Iperen, E. P. A., Sivapalaratnam, S., Tragante, V., Lanktree, M. B., Lange, L. A., Almoguera, B., Appelman, Y. E., Barnard, J., Baumert, J., Beitelshees, A. L., Bhangale, T. R., Chen, Y.-D. I., Gaunt, T. R., Gong, Y., Hopewell, J. C., Johnson, T., Kleber, M. E., ... LifeLines Cohort Study (2012). Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. American Journal of Human Genetics, 91(5), 823-838. https://doi.org/10.1016/j.ajhg.2012.08.032

@article{73e0f7b27fd642428bc13c99b8c16ab9,

title = "Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci",

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.",

author = "Asselbergs, {Folkert W} and Yiran Guo and {van Iperen}, {Erik P A} and Suthesh Sivapalaratnam and Vinicius Tragante and Lanktree, {Matthew B} and Lange, {Leslie A} and Berta Almoguera and Appelman, {Yolande E} and John Barnard and Jens Baumert and Beitelshees, {Amber L} and Bhangale, {Tushar R} and Chen, {Yii-Der Ida} and Gaunt, {Tom R} and Yan Gong and Hopewell, {Jemma C} and Toby Johnson and Kleber, {Marcus E} and Langaee, {Taimour Y} and Mingyao Li and Li, {Yun R} and Kiang Liu and McDonough, {Caitrin W} and Meijs, {Matthijs F L} and Middelberg, {Rita P S} and Kiran Musunuru and Nelson, {Christopher P} and O'Connell, {Jeffery R} and Sandosh Padmanabhan and Pankow, {James S} and Nathan Pankratz and Suzanne Rafelt and Ramakrishnan Rajagopalan and Romaine, {Simon P R} and Schork, {Nicholas J} and Jonathan Shaffer and Haiqing Shen and Smith, {Erin N} and Tischfield, {Sam E} and {van der Most}, {Peter J} and {van Vliet-Ostaptchouk}, {Jana V} and Niek Verweij and Volcik, {Kelly A} and Li Zhang and Bailey, {Kent R} and Mika Kivimaki and Day, {Ian N M} and Lawlor, {Debbie A} and Fotios Drenos and {LifeLines Cohort Study}",

year = "2012",

month = nov,

day = "2",

doi = "10.1016/j.ajhg.2012.08.032",

language = "English",

volume = "91",

pages = "823--838",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "5",

}

Asselbergs, FW, Guo, Y, van Iperen, EPA, Sivapalaratnam, S, Tragante, V, Lanktree, MB, Lange, LA, Almoguera, B, Appelman, YE, Barnard, J, Baumert, J, Beitelshees, AL, Bhangale, TR, Chen, Y-DI, Gaunt, TR, Gong, Y, Hopewell, JC, Johnson, T, Kleber, ME, Langaee, TY, Li, M, Li, YR, Liu, K, McDonough, CW, Meijs, MFL, Middelberg, RPS, Musunuru, K, Nelson, CP, O'Connell, JR, Padmanabhan, S, Pankow, JS, Pankratz, N, Rafelt, S, Rajagopalan, R, Romaine, SPR, 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, Kivimaki, M, Day, INM, Lawlor, DA, Drenos, F & LifeLines Cohort Study 2012, 'Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci', American Journal of Human Genetics, vol. 91, no. 5, pp. 823-838. https://doi.org/10.1016/j.ajhg.2012.08.032

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 F L

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 - Kivimaki, Mika

AU - Day, Ian N M

AU - Lawlor, Debbie A

AU - Drenos, Fotios

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 ∼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.

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 ∼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.

UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84868470681&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2012.08.032

DO - 10.1016/j.ajhg.2012.08.032

M3 - Article (Academic Journal)

C2 - 23063622

SN - 0002-9297

VL - 91

SP - 823

EP - 838

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 5

ER -

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

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