Genetic architecture of circulating lipid levels

Ayşe Demirkan, Najaf Amin, Aaron Isaacs, Marjo-Riitta Jarvelin, John B Whitfield, Heinz-Erich Wichmann, Kirsten O H M Kyvik, Igor Rudan, Christian Gieger, Andrew A Hicks, Åsa Johansson, Jouke-Jan Hottenga, Johannes J Smith, Sarah H Wild, Nancy L Pedersen, Gonneke Willemsen, Massimo Mangino, Caroline Hayward, André G Uitterlinden, Albert Hofman & 27 others Jacqueline Witteman, Grant W Montgomery, Kirsi H Pietiläinen, Taina Rantanen, Jaakko Kaprio, Angela Döring, Peter P Pramstaller, Ulf Gyllensten, Eco J C de Geus, Brenda W Penninx, James Wilson, Fernando Rivadeneria, Patrik K E Magnusson, Dorret I Boomsma, Tim Spector, Harry Campbell, Birgit Hoehne, Nicholas G Martin, Ben A Oostra, Mark McCarthy, Leena Peltonen-Palotie, Yurii Aulchenko, Peter M Visscher, Samuli Ripatti, A Cecile J W Janssens, Cornelia M van Duijn, ENGAGE Consortium

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
Original languageEnglish
JournalEuropean Journal of Human Genetics
Volume19
Issue number7
Pages (from-to)813-9
Number of pages7
ISSN1018-4813
DOIs
Publication statusPublished - 1. Jul 2011

Fingerprint

Lipids
Genome-Wide Association Study
LDL Cholesterol
HDL Cholesterol
Serum
Sample Size
Population

Keywords

  • Female
  • Genome-Wide Association Study
  • Humans
  • Lipid Metabolism
  • Lipids
  • Male
  • Metabolic Networks and Pathways
  • Models, Genetic
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Risk

Cite this

Demirkan, A., Amin, N., Isaacs, A., Jarvelin, M-R., Whitfield, J. B., Wichmann, H-E., ... ENGAGE Consortium (2011). Genetic architecture of circulating lipid levels. European Journal of Human Genetics, 19(7), 813-9. https://doi.org/10.1038/ejhg.2011.21
Demirkan, Ayşe ; Amin, Najaf ; Isaacs, Aaron ; Jarvelin, Marjo-Riitta ; Whitfield, John B ; Wichmann, Heinz-Erich ; Kyvik, Kirsten O H M ; Rudan, Igor ; Gieger, Christian ; Hicks, Andrew A ; Johansson, Åsa ; Hottenga, Jouke-Jan ; Smith, Johannes J ; Wild, Sarah H ; Pedersen, Nancy L ; Willemsen, Gonneke ; Mangino, Massimo ; Hayward, Caroline ; Uitterlinden, André G ; Hofman, Albert ; Witteman, Jacqueline ; Montgomery, Grant W ; Pietiläinen, Kirsi H ; Rantanen, Taina ; Kaprio, Jaakko ; Döring, Angela ; Pramstaller, Peter P ; Gyllensten, Ulf ; de Geus, Eco J C ; Penninx, Brenda W ; Wilson, James ; Rivadeneria, Fernando ; Magnusson, Patrik K E ; Boomsma, Dorret I ; Spector, Tim ; Campbell, Harry ; Hoehne, Birgit ; Martin, Nicholas G ; Oostra, Ben A ; McCarthy, Mark ; Peltonen-Palotie, Leena ; Aulchenko, Yurii ; Visscher, Peter M ; Ripatti, Samuli ; Janssens, A Cecile J W ; van Duijn, Cornelia M ; ENGAGE Consortium. / Genetic architecture of circulating lipid levels. In: European Journal of Human Genetics. 2011 ; Vol. 19, No. 7. pp. 813-9.
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abstract = "Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.",
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Demirkan, A, Amin, N, Isaacs, A, Jarvelin, M-R, Whitfield, JB, Wichmann, H-E, Kyvik, KOHM, Rudan, I, Gieger, C, Hicks, AA, Johansson, Å, Hottenga, J-J, Smith, JJ, Wild, SH, Pedersen, NL, Willemsen, G, Mangino, M, Hayward, C, Uitterlinden, AG, Hofman, A, Witteman, J, Montgomery, GW, Pietiläinen, KH, Rantanen, T, Kaprio, J, Döring, A, Pramstaller, PP, Gyllensten, U, de Geus, EJC, Penninx, BW, Wilson, J, Rivadeneria, F, Magnusson, PKE, Boomsma, DI, Spector, T, Campbell, H, Hoehne, B, Martin, NG, Oostra, BA, McCarthy, M, Peltonen-Palotie, L, Aulchenko, Y, Visscher, PM, Ripatti, S, Janssens, ACJW, van Duijn, CM & ENGAGE Consortium 2011, 'Genetic architecture of circulating lipid levels', European Journal of Human Genetics, vol. 19, no. 7, pp. 813-9. https://doi.org/10.1038/ejhg.2011.21

Genetic architecture of circulating lipid levels. / Demirkan, Ayşe; Amin, Najaf; Isaacs, Aaron; Jarvelin, Marjo-Riitta; Whitfield, John B; Wichmann, Heinz-Erich; Kyvik, Kirsten O H M; Rudan, Igor; Gieger, Christian; Hicks, Andrew A; Johansson, Åsa; Hottenga, Jouke-Jan; Smith, Johannes J; Wild, Sarah H; Pedersen, Nancy L; Willemsen, Gonneke; Mangino, Massimo; Hayward, Caroline; Uitterlinden, André G; Hofman, Albert; Witteman, Jacqueline; Montgomery, Grant W; Pietiläinen, Kirsi H; Rantanen, Taina; Kaprio, Jaakko; Döring, Angela; Pramstaller, Peter P; Gyllensten, Ulf; de Geus, Eco J C; Penninx, Brenda W; Wilson, James; Rivadeneria, Fernando; Magnusson, Patrik K E; Boomsma, Dorret I; Spector, Tim; Campbell, Harry; Hoehne, Birgit; Martin, Nicholas G; Oostra, Ben A; McCarthy, Mark; Peltonen-Palotie, Leena; Aulchenko, Yurii; Visscher, Peter M; Ripatti, Samuli; Janssens, A Cecile J W; van Duijn, Cornelia M; ENGAGE Consortium.

In: European Journal of Human Genetics, Vol. 19, No. 7, 01.07.2011, p. 813-9.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Genetic architecture of circulating lipid levels

AU - Demirkan, Ayşe

AU - Amin, Najaf

AU - Isaacs, Aaron

AU - Jarvelin, Marjo-Riitta

AU - Whitfield, John B

AU - Wichmann, Heinz-Erich

AU - Kyvik, Kirsten O H M

AU - Rudan, Igor

AU - Gieger, Christian

AU - Hicks, Andrew A

AU - Johansson, Åsa

AU - Hottenga, Jouke-Jan

AU - Smith, Johannes J

AU - Wild, Sarah H

AU - Pedersen, Nancy L

AU - Willemsen, Gonneke

AU - Mangino, Massimo

AU - Hayward, Caroline

AU - Uitterlinden, André G

AU - Hofman, Albert

AU - Witteman, Jacqueline

AU - Montgomery, Grant W

AU - Pietiläinen, Kirsi H

AU - Rantanen, Taina

AU - Kaprio, Jaakko

AU - Döring, Angela

AU - Pramstaller, Peter P

AU - Gyllensten, Ulf

AU - de Geus, Eco J C

AU - Penninx, Brenda W

AU - Wilson, James

AU - Rivadeneria, Fernando

AU - Magnusson, Patrik K E

AU - Boomsma, Dorret I

AU - Spector, Tim

AU - Campbell, Harry

AU - Hoehne, Birgit

AU - Martin, Nicholas G

AU - Oostra, Ben A

AU - McCarthy, Mark

AU - Peltonen-Palotie, Leena

AU - Aulchenko, Yurii

AU - Visscher, Peter M

AU - Ripatti, Samuli

AU - Janssens, A Cecile J W

AU - van Duijn, Cornelia M

AU - ENGAGE Consortium

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

AB - Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Lipid Metabolism

KW - Lipids

KW - Male

KW - Metabolic Networks and Pathways

KW - Models, Genetic

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Risk

U2 - 10.1038/ejhg.2011.21

DO - 10.1038/ejhg.2011.21

M3 - Journal article

VL - 19

SP - 813

EP - 819

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 7

ER -

Demirkan A, Amin N, Isaacs A, Jarvelin M-R, Whitfield JB, Wichmann H-E et al. Genetic architecture of circulating lipid levels. European Journal of Human Genetics. 2011 Jul 1;19(7):813-9. https://doi.org/10.1038/ejhg.2011.21