Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan; Cristen J. Willer; Gina M. Peloso; Serkalem Demissie; Kiran Musunuru; Eric E. Schadt; Lee Kaplan; Derrick Bennett; Yun Li; Toshiko Tanaka; Benjamin F. Voight; Lori L. Bonnycastle; Anne U. Jackson; Gabriel Crawford; Aarti Surti; Candace Guiducci; Noel P. Burtt; Sarah Parish; Robert Clarke; Diana Zelenika; Kari A. Kubalanza; Mario A. Morken; Laura J. Scott; Heather M. Stringham; Pilar Galan; Amy J. Swift; Johanna Kuusisto; Richard N. Bergman; Jouko Sundvall; Markku Laakso; Luigi Ferrucci; Paul Scheet; Serena Sanna; Manuela Uda; Qiong Yang; Kathryn L. Lunetta; Josee Dupuis; Paul I. W. de Bakker; Christopher J. O'Donnell; John C. Chambers; Jaspal S. Kooner; Serge Hercberg; Pierre Meneton; Edward G. Lakatta; Angelo Scuteri; David Schlessinger; Jaakko Tuomilehto; Francis S. Collins; Leif Groop; David Altshuler; Rory Collins; G. Mark Lathrop; Olle Melander; Veikko Salomaa; Leena Peltonen; Marju Orho-Melander; Jose M. Ordovas; Michael Boehnke; Goncalo R. Abecasis; Karen L. Mohlke; L. Adrienne Cupples

doi:10.1038/ng.291

Common variants at 30 loci contribute to polygenic dyslipidemia

Sekar Kathiresan, Cristen J. Willer, Gina M. Peloso, Serkalem Demissie, Kiran Musunuru, Eric E. Schadt, Lee Kaplan, Derrick Bennett, Yun Li, Toshiko Tanaka, Benjamin F. Voight, Lori L. Bonnycastle, Anne U. Jackson, Gabriel Crawford, Aarti Surti, Candace Guiducci, Noel P. Burtt, Sarah Parish, Robert Clarke, Diana ZelenikaKari A. Kubalanza, Mario A. Morken, Laura J. Scott, Heather M. Stringham, Pilar Galan, Amy J. Swift, Johanna Kuusisto, Richard N. Bergman, Jouko Sundvall, Markku Laakso, Luigi Ferrucci, Paul Scheet, Serena Sanna, Manuela Uda, Qiong Yang, Kathryn L. Lunetta, Josee Dupuis, Paul I. W. de Bakker, Christopher J. O'Donnell, John C. Chambers, Jaspal S. Kooner, Serge Hercberg, Pierre Meneton, Edward G. Lakatta, Angelo Scuteri, David Schlessinger, Jaakko Tuomilehto, Francis S. Collins, Leif Groop, David Altshuler, Rory Collins, G. Mark Lathrop, Olle Melander, Veikko Salomaa, Leena Peltonen, Marju Orho-Melander, Jose M. Ordovas, Michael Boehnke, Goncalo R. Abecasis, Karen L. Mohlke, L. Adrienne Cupples

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Abstract

Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Original language	English
Pages (from-to)	56-65
Journal	Nature Genetics
Volume	41
Issue number	1
DOIs	https://doi.org/10.1038/ng.291
Publication status	Published - 2009

Subject classification (UKÄ)

Endocrinology and Diabetes
Cardiology and Cardiovascular Disease

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.291

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Kathiresan, S., Willer, C. J., Peloso, G. M., Demissie, S., Musunuru, K., Schadt, E. E., Kaplan, L., Bennett, D., Li, Y., Tanaka, T., Voight, B. F., Bonnycastle, L. L., Jackson, A. U., Crawford, G., Surti, A., Guiducci, C., Burtt, N. P., Parish, S., Clarke, R., ... Cupples, L. A. (2009). Common variants at 30 loci contribute to polygenic dyslipidemia. Nature Genetics, 41(1), 56-65. https://doi.org/10.1038/ng.291

@article{3bda50e8bbd14784a049cf6d1364419b,

title = "Common variants at 30 loci contribute to polygenic dyslipidemia",

abstract = "Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.",

author = "Sekar Kathiresan and Willer, {Cristen J.} and Peloso, {Gina M.} and Serkalem Demissie and Kiran Musunuru and Schadt, {Eric E.} and Lee Kaplan and Derrick Bennett and Yun Li and Toshiko Tanaka and Voight, {Benjamin F.} and Bonnycastle, {Lori L.} and Jackson, {Anne U.} and Gabriel Crawford and Aarti Surti and Candace Guiducci and Burtt, {Noel P.} and Sarah Parish and Robert Clarke and Diana Zelenika and Kubalanza, {Kari A.} and Morken, {Mario A.} and Scott, {Laura J.} and Stringham, {Heather M.} and Pilar Galan and Swift, {Amy J.} and Johanna Kuusisto and Bergman, {Richard N.} and Jouko Sundvall and Markku Laakso and Luigi Ferrucci and Paul Scheet and Serena Sanna and Manuela Uda and Qiong Yang and Lunetta, {Kathryn L.} and Josee Dupuis and {de Bakker}, {Paul I. W.} and O'Donnell, {Christopher J.} and Chambers, {John C.} and Kooner, {Jaspal S.} and Serge Hercberg and Pierre Meneton and Lakatta, {Edward G.} and Angelo Scuteri and David Schlessinger and Jaakko Tuomilehto and Collins, {Francis S.} and Leif Groop and David Altshuler and Rory Collins and Lathrop, {G. Mark} and Olle Melander and Veikko Salomaa and Leena Peltonen and Marju Orho-Melander and Ordovas, {Jose M.} and Michael Boehnke and Abecasis, {Goncalo R.} and Mohlke, {Karen L.} and Cupples, {L. Adrienne}",

year = "2009",

doi = "10.1038/ng.291",

language = "English",

volume = "41",

pages = "56--65",

journal = "Nature Genetics",

issn = "1546-1718",

publisher = "Nature Publishing Group",

number = "1",

}

Kathiresan, S, Willer, CJ, Peloso, GM, Demissie, S, Musunuru, K, Schadt, EE, Kaplan, L, Bennett, D, Li, Y, Tanaka, T, Voight, BF, Bonnycastle, LL, Jackson, AU, Crawford, G, Surti, A, Guiducci, C, Burtt, NP, Parish, S, Clarke, R, Zelenika, D, Kubalanza, KA, Morken, MA, Scott, LJ, Stringham, HM, Galan, P, Swift, AJ, Kuusisto, J, Bergman, RN, Sundvall, J, Laakso, M, Ferrucci, L, Scheet, P, Sanna, S, Uda, M, Yang, Q, Lunetta, KL, Dupuis, J, de Bakker, PIW, O'Donnell, CJ, Chambers, JC, Kooner, JS, Hercberg, S, Meneton, P, Lakatta, EG, Scuteri, A, Schlessinger, D, Tuomilehto, J, Collins, FS, Groop, L, Altshuler, D, Collins, R, Lathrop, GM, Melander, O, Salomaa, V, Peltonen, L, Orho-Melander, M, Ordovas, JM, Boehnke, M, Abecasis, GR, Mohlke, KL & Cupples, LA 2009, 'Common variants at 30 loci contribute to polygenic dyslipidemia', Nature Genetics, vol. 41, no. 1, pp. 56-65. https://doi.org/10.1038/ng.291

TY - JOUR

T1 - Common variants at 30 loci contribute to polygenic dyslipidemia

AU - Kathiresan, Sekar

AU - Willer, Cristen J.

AU - Peloso, Gina M.

AU - Demissie, Serkalem

AU - Musunuru, Kiran

AU - Schadt, Eric E.

AU - Kaplan, Lee

AU - Bennett, Derrick

AU - Li, Yun

AU - Tanaka, Toshiko

AU - Voight, Benjamin F.

AU - Bonnycastle, Lori L.

AU - Jackson, Anne U.

AU - Crawford, Gabriel

AU - Surti, Aarti

AU - Guiducci, Candace

AU - Burtt, Noel P.

AU - Parish, Sarah

AU - Clarke, Robert

AU - Zelenika, Diana

AU - Kubalanza, Kari A.

AU - Morken, Mario A.

AU - Scott, Laura J.

AU - Stringham, Heather M.

AU - Galan, Pilar

AU - Swift, Amy J.

AU - Kuusisto, Johanna

AU - Bergman, Richard N.

AU - Sundvall, Jouko

AU - Laakso, Markku

AU - Ferrucci, Luigi

AU - Scheet, Paul

AU - Sanna, Serena

AU - Uda, Manuela

AU - Yang, Qiong

AU - Lunetta, Kathryn L.

AU - Dupuis, Josee

AU - de Bakker, Paul I. W.

AU - O'Donnell, Christopher J.

AU - Chambers, John C.

AU - Kooner, Jaspal S.

AU - Hercberg, Serge

AU - Meneton, Pierre

AU - Lakatta, Edward G.

AU - Scuteri, Angelo

AU - Schlessinger, David

AU - Tuomilehto, Jaakko

AU - Collins, Francis S.

AU - Groop, Leif

AU - Altshuler, David

AU - Collins, Rory

AU - Lathrop, G. Mark

AU - Melander, Olle

AU - Salomaa, Veikko

AU - Peltonen, Leena

AU - Orho-Melander, Marju

AU - Ordovas, Jose M.

AU - Boehnke, Michael

AU - Abecasis, Goncalo R.

AU - Mohlke, Karen L.

AU - Cupples, L. Adrienne

PY - 2009

Y1 - 2009

N2 - Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

AB - Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

U2 - 10.1038/ng.291

DO - 10.1038/ng.291

M3 - Article

C2 - 19060906

SN - 1546-1718

VL - 41

SP - 56

EP - 65

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Common variants at 30 loci contribute to polygenic dyslipidemia

Abstract

Subject classification (UKÄ)

UN SDGs

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