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; Josée 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; Gonçalo 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, Josée 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, Gonçalo R. Abecasis, Karen L. Mohlke, L. Adrienne Cupples

Research output: Contribution to journal › Article › peer-review

1126 Scopus citations

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 × 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 (US)
Pages (from-to)	56-65
Number of pages	10
Journal	Nature Genetics
Volume	41
Issue number	1
DOIs	https://doi.org/10.1038/ng.291
State	Published - Jan 2009
Externally published	Yes

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/ng.291

Cite this

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

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

@article{42bc26e63dbf406f8253b117bb1af298,

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 × 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 Jos{\'e}e 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, {Gon{\c c}alo R.} and Mohlke, {Karen L.} and Cupples, {L. Adrienne}",

note = "Funding Information: The SardiNIA authors thank the many volunteers who generously participated in these studies. This work was supported in part by the Intramural Research Program of the National Institute on Aging and by extramural grants from the National Human Genome Research Institute (HG02651) and the NHLBI (HL084729). Additional support was provided by the mayors, administrations and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. G.R.A. is a Pew Scholar for the Biomedical Sciences. FINRISK97 author L.P. is supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland and the Nordic Center of Excellence in Disease Genetics. V.S. was supported by the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research. The ISIS trials and epidemiological studies were supported by the manufacturers of the study drugs and by the British Heart Foundation, Medical Research Council, Cancer Research UK, Tobacco Products Research Trust of the UK Department of Health Independent Scientific Committee on Smoking and Health, and the Oxford Genetics Knowledge Park. Funding Information: The FHS authors thank the FHS participants for their long-term voluntary commitment to this study. The FHS is supported by a contract from the National Heart, Lung and Blood Institute (NHLBI; contract no. N01-HC-25195). The NHLBI{\textquoteright}s SNP Health Association Resource research program supported the FHS genotyping. J.M.O. is supported by NHLBI grant HL-54776 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service. The DGI and MDC-CC authors thank R. Saxena, V. Lyssenko, M. Daly, J. Hirschhorn, S. Gabriel, H. Chen, T. Hughes, the entire DGI study team and the Botnia Study team for their roles in sample collection, phenotyping, design and conduct of the DGI study; and M. Svenson and L. Rosberg for technical assistance in Malm{\"o}. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the United States National Institutes of Health (NIH) and institutional support from the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. L.G. is supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd. His work in Malm{\"o}, Sweden, was also funded by a Linn{\'e} grant from the Swedish Medical Research Council. M.O.-M. is supported by a European Foundation for the Study of Diabetes–Pfizer grant and the Novo Nordisk Foundation. M.O.-M. and O.M. are supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malm{\"o} University Hospital, the Albert P{\aa}hlsson Research Foundation and the Crafoord Foundation. O.M. is also supported by the Swedish Medical Society, the Ernhold Lundstr{\"o}ms Research Foundation, the Mossfelt Foundation, the King Gustav V and Queen Victoria Foundation and the Region Skane. Funding Information: The FUSION and METSIM authors thank the Finnish citizens who generously participated in these studies. Support for FUSION was provided by NIH grants DK062370 (to M.B.) and DK072193 (to K.L.M.), intramural project number 1Z01 HG000024 (to F.S.C.) and a postdoctoral fellowship award from the American Diabetes Association (to C.J.W.). K.L.M. is a Pew Scholar for the Biomedical Sciences. Genome-wide genotyping was conducted by the Johns Hopkins University Genetic Resources Core Facility SNP Center at the Center for Inherited Disease Research (CIDR), with support from CIDR NIH contract no. N01-HG-65403. Support for METSIM was provided by grant 124243 from the Academy of Finland (to M.L.).",

year = "2009",

month = jan,

doi = "10.1038/ng.291",

language = "English (US)",

volume = "41",

pages = "56--65",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "1",

}

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, Josée

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, Gonçalo R.

AU - Mohlke, Karen L.

AU - Cupples, L. Adrienne

N1 - Funding Information: The SardiNIA authors thank the many volunteers who generously participated in these studies. This work was supported in part by the Intramural Research Program of the National Institute on Aging and by extramural grants from the National Human Genome Research Institute (HG02651) and the NHLBI (HL084729). Additional support was provided by the mayors, administrations and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. G.R.A. is a Pew Scholar for the Biomedical Sciences. FINRISK97 author L.P. is supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland and the Nordic Center of Excellence in Disease Genetics. V.S. was supported by the Sigrid Juselius Foundation and the Finnish Foundation for Cardiovascular Research. The ISIS trials and epidemiological studies were supported by the manufacturers of the study drugs and by the British Heart Foundation, Medical Research Council, Cancer Research UK, Tobacco Products Research Trust of the UK Department of Health Independent Scientific Committee on Smoking and Health, and the Oxford Genetics Knowledge Park. Funding Information: The FHS authors thank the FHS participants for their long-term voluntary commitment to this study. The FHS is supported by a contract from the National Heart, Lung and Blood Institute (NHLBI; contract no. N01-HC-25195). The NHLBI’s SNP Health Association Resource research program supported the FHS genotyping. J.M.O. is supported by NHLBI grant HL-54776 and by contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service. The DGI and MDC-CC authors thank R. Saxena, V. Lyssenko, M. Daly, J. Hirschhorn, S. Gabriel, H. Chen, T. Hughes, the entire DGI study team and the Botnia Study team for their roles in sample collection, phenotyping, design and conduct of the DGI study; and M. Svenson and L. Rosberg for technical assistance in Malmö. S.K. is supported by a Doris Duke Charitable Foundation Clinical Scientist Development Award, a charitable gift from the Fannie E. Rippel Foundation, the Donovan Family Foundation, a career development award from the United States National Institutes of Health (NIH) and institutional support from the Department of Medicine and Cardiovascular Research Center at Massachusetts General Hospital. L.G. is supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd. His work in Malmö, Sweden, was also funded by a Linné grant from the Swedish Medical Research Council. M.O.-M. is supported by a European Foundation for the Study of Diabetes–Pfizer grant and the Novo Nordisk Foundation. M.O.-M. and O.M. are supported by the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Medical Faculty of Lund University, Malmö University Hospital, the Albert Påhlsson Research Foundation and the Crafoord Foundation. O.M. is also supported by the Swedish Medical Society, the Ernhold Lundströms Research Foundation, the Mossfelt Foundation, the King Gustav V and Queen Victoria Foundation and the Region Skane. Funding Information: The FUSION and METSIM authors thank the Finnish citizens who generously participated in these studies. Support for FUSION was provided by NIH grants DK062370 (to M.B.) and DK072193 (to K.L.M.), intramural project number 1Z01 HG000024 (to F.S.C.) and a postdoctoral fellowship award from the American Diabetes Association (to C.J.W.). K.L.M. is a Pew Scholar for the Biomedical Sciences. Genome-wide genotyping was conducted by the Johns Hopkins University Genetic Resources Core Facility SNP Center at the Center for Inherited Disease Research (CIDR), with support from CIDR NIH contract no. N01-HG-65403. Support for METSIM was provided by grant 124243 from the Academy of Finland (to M.L.).

PY - 2009/1

Y1 - 2009/1

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 × 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 × 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.

UR - http://www.scopus.com/inward/record.url?scp=58149163149&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149163149&partnerID=8YFLogxK

U2 - 10.1038/ng.291

DO - 10.1038/ng.291

M3 - Article

C2 - 19060906

AN - SCOPUS:58149163149

SN - 1061-4036

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

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this