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 & 31 others Mingyao Li, Yun R. Li, Kiang Liu, Caitrin W. McDonough, Matthijs El. 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, Kristian M. Bailey, Florianne Bauer, Jolanda M. A. Boer, John M. Connell, LifeLines Cohort Study

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)823-838
Number of pages16
JournalAmerican Journal of Human Genetics
Volume91
Issue number5
DOIs
Publication statusPublished - 2 Nov 2012

Keywords

  • COMPLEX TRAITS
  • DENSITY-LIPOPROTEIN CHOLESTEROL
  • GENOME-WIDE ASSOCIATION
  • PLASMA TRIGLYCERIDES
  • FAMILIAL HYPERCHOLESTEROLEMIA
  • MISSING HERITABILITY
  • QUANTITATIVE TRAITS
  • STATISTICAL-MODEL
  • APOLIPOPROTEIN B-100
  • CORONARY-HEART-DISEASE

Cite this

Asselbergs, F. W., Guo, Y., van Iperen, E. P. A., Sivapalaratnam, S., Tragante, V., Lanktree, M. B., ... 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
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 El. ; Middelberg, Rita P. S. ; Musunuru, Kiran ; Nelson, Christopher P. ; O'Connell, Jeffery R. ; Padmanabhan, Sandosh ; Pankow, James S. ; Pankratz, Nathan ; Rafelt, Suzanne ; Rajagopalan, Ramakrishnan ; Romaine, Simon P. R. ; Schork, Nicholas J. ; Shaffer, Jonathan ; Shen, Haiqing ; Smith, Erin N. ; Tischfield, Sam E. ; van der Most, Peter J. ; van Vliet-Ostaptchouk, Jana V. ; Verweij, Niek ; Volcik, Kelly A. ; Zhang, Li ; Bailey, Kent R. ; Bailey, Kristian M. ; Bauer, Florianne ; Boer, Jolanda M. A. ; Connell, John M. ; LifeLines Cohort Study. / Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. In: American Journal of Human Genetics. 2012 ; Vol. 91, No. 5. pp. 823-838.
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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 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.",
keywords = "COMPLEX TRAITS, DENSITY-LIPOPROTEIN CHOLESTEROL, GENOME-WIDE ASSOCIATION, PLASMA TRIGLYCERIDES, FAMILIAL HYPERCHOLESTEROLEMIA, MISSING HERITABILITY, QUANTITATIVE TRAITS, STATISTICAL-MODEL, APOLIPOPROTEIN B-100, CORONARY-HEART-DISEASE",
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 El.} 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 Bailey, {Kristian M.} and Florianne Bauer and Boer, {Jolanda M. A.} and Connell, {John M.} and {LifeLines Cohort Study}",
year = "2012",
month = "11",
day = "2",
doi = "10.1016/j.ajhg.2012.08.032",
language = "English",
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pages = "823--838",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
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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, ME, 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, Bailey, KM, Bauer, F, Boer, JMA, Connell, JM & 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

Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. / 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 El.; Middelberg, Rita P. S.; Musunuru, Kiran; Nelson, Christopher P.; O'Connell, Jeffery R.; Padmanabhan, Sandosh; Pankow, James S.; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P. R.; Schork, Nicholas J.; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N.; Tischfield, Sam E.; van der Most, Peter J.; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Volcik, Kelly A.; Zhang, Li; Bailey, Kent R.; Bailey, Kristian M.; Bauer, Florianne; Boer, Jolanda M. A.; Connell, John M.; LifeLines Cohort Study.

In: American Journal of Human Genetics, Vol. 91, No. 5, 02.11.2012, p. 823-838.

Research output: Contribution to journalArticle

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

VL - 91

SP - 823

EP - 838

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -

Asselbergs FW, Guo Y, van Iperen EPA, Sivapalaratnam S, Tragante V, Lanktree MB et al. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci. American Journal of Human Genetics. 2012 Nov 2;91(5):823-838. https://doi.org/10.1016/j.ajhg.2012.08.032