Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Cristen J. Willer; Serena Sanna; Anne U. Jackson; Angelo Scuteri; Lori L. Bonnycastle; Robert Clarke; Simon C. Heath; Nicholas J. Timpson; Samer S. Najjar; Heather M. Stringham; James Strait; William L. Duren; Andrea Maschio; Fabio Busonero; Antonella Mulas; Giuseppe Albai; Amy J. Swift; Mario A. Morken; Narisu Narisu; Derrick Bennett; Sarah Parish; Haiqing Shen; Pilar Galan; Pierre Meneton; Serge Hercberg; Diana Zelenika; Wei Min Chen; Yun Li; Laura J. Scott; Paul A. Scheet; Jouko Sundvall; Richard M. Watanabe; Ramaiah Nagaraja; Shah Ebrahim; Debbie A. Lawlor; Yoav Ben-Shlomo; George Davey-Smith; Alan R. Shuldiner; Rory Collins; Richard N. Bergman; Manuela Uda; Jaakko Tuomilehto; Antonio Cao; Francis S. Collins; Edward Lakatta; G. Mark Lathrop; Michael Boehnke; David Schlessinger; Karen L. Mohlke; Gonçalo R. Abecasis

doi:10.1038/ng.76

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

Cristen J. Willer, Serena Sanna, Anne U. Jackson, Angelo Scuteri, Lori L. Bonnycastle, Robert Clarke, Simon C. Heath, Nicholas J. Timpson, Samer S. Najjar, Heather M. Stringham, James Strait, William L. Duren, Andrea Maschio, Fabio Busonero, Antonella Mulas, Giuseppe Albai, Amy J. Swift, Mario A. Morken, Narisu Narisu, Derrick BennettSarah Parish, Haiqing Shen, Pilar Galan, Pierre Meneton, Serge Hercberg, Diana Zelenika, Wei Min Chen, Yun Li, Laura J. Scott, Paul A. Scheet, Jouko Sundvall, Richard M. Watanabe, Ramaiah Nagaraja, Shah Ebrahim, Debbie A. Lawlor, Yoav Ben-Shlomo, George Davey-Smith, Alan R. Shuldiner, Rory Collins, Richard N. Bergman, Manuela Uda, Jaakko Tuomilehto, Antonio Cao, Francis S. Collins, Edward Lakatta, G. Mark Lathrop, Michael Boehnke, David Schlessinger, Karen L. Mohlke, Gonçalo R. Abecasis

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Abstract

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

Original language	English (US)
Pages (from-to)	161-169
Number of pages	9
Journal	Nature Genetics
Volume	40
Issue number	2
DOIs	https://doi.org/10.1038/ng.76
State	Published - Feb 2008
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Willer, C. J., Sanna, S., Jackson, A. U., Scuteri, A., Bonnycastle, L. L., Clarke, R., Heath, S. C., Timpson, N. J., Najjar, S. S., Stringham, H. M., Strait, J., Duren, W. L., Maschio, A., Busonero, F., Mulas, A., Albai, G., Swift, A. J., Morken, M. A., Narisu, N., ... Abecasis, G. R. (2008). Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature Genetics, 40(2), 161-169. https://doi.org/10.1038/ng.76

Willer, CJ, Sanna, S, Jackson, AU, Scuteri, A, Bonnycastle, LL, Clarke, R, Heath, SC, Timpson, NJ, Najjar, SS, Stringham, HM, Strait, J, Duren, WL, Maschio, A, Busonero, F, Mulas, A, Albai, G, Swift, AJ, Morken, MA, Narisu, N, Bennett, D, Parish, S, Shen, H, Galan, P, Meneton, P, Hercberg, S, Zelenika, D, Chen, WM, Li, Y, Scott, LJ, Scheet, PA, Sundvall, J, Watanabe, RM, Nagaraja, R, Ebrahim, S, Lawlor, DA, Ben-Shlomo, Y, Davey-Smith, G, Shuldiner, AR, Collins, R, Bergman, RN, Uda, M, Tuomilehto, J, Cao, A, Collins, FS, Lakatta, E, Lathrop, GM, Boehnke, M, Schlessinger, D, Mohlke, KL & Abecasis, GR 2008, 'Newly identified loci that influence lipid concentrations and risk of coronary artery disease', Nature Genetics, vol. 40, no. 2, pp. 161-169. https://doi.org/10.1038/ng.76

@article{54f843c6458d45f99d2640cc85467512,

title = "Newly identified loci that influence lipid concentrations and risk of coronary artery disease",

abstract = "To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.",

author = "Willer, {Cristen J.} and Serena Sanna and Jackson, {Anne U.} and Angelo Scuteri and Bonnycastle, {Lori L.} and Robert Clarke and Heath, {Simon C.} and Timpson, {Nicholas J.} and Najjar, {Samer S.} and Stringham, {Heather M.} and James Strait and Duren, {William L.} and Andrea Maschio and Fabio Busonero and Antonella Mulas and Giuseppe Albai and Swift, {Amy J.} and Morken, {Mario A.} and Narisu Narisu and Derrick Bennett and Sarah Parish and Haiqing Shen and Pilar Galan and Pierre Meneton and Serge Hercberg and Diana Zelenika and Chen, {Wei Min} and Yun Li and Scott, {Laura J.} and Scheet, {Paul A.} and Jouko Sundvall and Watanabe, {Richard M.} and Ramaiah Nagaraja and Shah Ebrahim and Lawlor, {Debbie A.} and Yoav Ben-Shlomo and George Davey-Smith and Shuldiner, {Alan R.} and Rory Collins and Bergman, {Richard N.} and Manuela Uda and Jaakko Tuomilehto and Antonio Cao and Collins, {Francis S.} and Edward Lakatta and Lathrop, {G. Mark} and Michael Boehnke and David Schlessinger and Mohlke, {Karen L.} and Abecasis, {Gon{\c c}alo R.}",

note = "Funding Information: We are indebted to the many volunteers who generously participated in these studies. We thank our colleagues from the DGI for sharing prepublication data; M. Erdos, P. Chines, P. Deodhar, K. Kubalanza, A. Sprau and M. Tong of FUSION and E. Pugh, K. Doheny and Center for Inherited Disease Research (CIDR) investigators for expert technical work; N. Rosenberg for helpful discussions about population genetics; the SardiNIA Research Clinic staff; and the Amish Research Clinic staff. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data are available from the WTCCC website. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. The Caerphilly study was funded by the Medical Research Council (UK). The Caerphilly study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The data archive is maintained by the Department of Social Medicine, University of Bristol. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA), by extramural grants from National Human Genome Research Institute (NHGRI), the National Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart Lung and Blood Institute (NHLBI), by the American Diabetes Association, the Department of Veterans Affairs, the British Heart Foundation, the Medical Research Council of the United Kingdom and the French Ministry of Higher Education and Research. FUSION genome-wide genotyping was carried out by the Johns Hopkins University Genetic Resources Core Facility (GRCF) SNP Center at CIDR with support from CIDR NIH (contract N01-HG-65403) and the GRCF SNP Center. Additional support for the SardiNIA study was provided by the mayors, administration and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. C.J.W. is the recipient of a postdoctoral fellowship from the American Diabetes Association. G.R.A. and K.L.M. are Pew Scholars for the Biomedical Sciences.",

year = "2008",

month = feb,

doi = "10.1038/ng.76",

language = "English (US)",

volume = "40",

pages = "161--169",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Newly identified loci that influence lipid concentrations and risk of coronary artery disease

AU - Willer, Cristen J.

AU - Sanna, Serena

AU - Jackson, Anne U.

AU - Scuteri, Angelo

AU - Bonnycastle, Lori L.

AU - Clarke, Robert

AU - Heath, Simon C.

AU - Timpson, Nicholas J.

AU - Najjar, Samer S.

AU - Stringham, Heather M.

AU - Strait, James

AU - Duren, William L.

AU - Maschio, Andrea

AU - Busonero, Fabio

AU - Mulas, Antonella

AU - Albai, Giuseppe

AU - Swift, Amy J.

AU - Morken, Mario A.

AU - Narisu, Narisu

AU - Bennett, Derrick

AU - Parish, Sarah

AU - Shen, Haiqing

AU - Galan, Pilar

AU - Meneton, Pierre

AU - Hercberg, Serge

AU - Zelenika, Diana

AU - Chen, Wei Min

AU - Li, Yun

AU - Scott, Laura J.

AU - Scheet, Paul A.

AU - Sundvall, Jouko

AU - Watanabe, Richard M.

AU - Nagaraja, Ramaiah

AU - Ebrahim, Shah

AU - Lawlor, Debbie A.

AU - Ben-Shlomo, Yoav

AU - Davey-Smith, George

AU - Shuldiner, Alan R.

AU - Collins, Rory

AU - Bergman, Richard N.

AU - Uda, Manuela

AU - Tuomilehto, Jaakko

AU - Cao, Antonio

AU - Collins, Francis S.

AU - Lakatta, Edward

AU - Lathrop, G. Mark

AU - Boehnke, Michael

AU - Schlessinger, David

AU - Mohlke, Karen L.

AU - Abecasis, Gonçalo R.

N1 - Funding Information: We are indebted to the many volunteers who generously participated in these studies. We thank our colleagues from the DGI for sharing prepublication data; M. Erdos, P. Chines, P. Deodhar, K. Kubalanza, A. Sprau and M. Tong of FUSION and E. Pugh, K. Doheny and Center for Inherited Disease Research (CIDR) investigators for expert technical work; N. Rosenberg for helpful discussions about population genetics; the SardiNIA Research Clinic staff; and the Amish Research Clinic staff. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data are available from the WTCCC website. Funding for the WTCCC project was provided by the Wellcome Trust under award 076113. The Caerphilly study was funded by the Medical Research Council (UK). The Caerphilly study was undertaken by the former MRC Epidemiology Unit (South Wales) and was funded by the Medical Research Council of the United Kingdom. The data archive is maintained by the Department of Social Medicine, University of Bristol. This work was supported in part by the Intramural Research Program of the National Institute on Aging (NIA), by extramural grants from National Human Genome Research Institute (NHGRI), the National Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart Lung and Blood Institute (NHLBI), by the American Diabetes Association, the Department of Veterans Affairs, the British Heart Foundation, the Medical Research Council of the United Kingdom and the French Ministry of Higher Education and Research. FUSION genome-wide genotyping was carried out by the Johns Hopkins University Genetic Resources Core Facility (GRCF) SNP Center at CIDR with support from CIDR NIH (contract N01-HG-65403) and the GRCF SNP Center. Additional support for the SardiNIA study was provided by the mayors, administration and residents of Lanusei, Ilbono, Arzana and Elini and the head of Public Health Unit ASL4 in Sardinia. C.J.W. is the recipient of a postdoctoral fellowship from the American Diabetes Association. G.R.A. and K.L.M. are Pew Scholars for the Biomedical Sciences.

PY - 2008/2

Y1 - 2008/2

N2 - To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

AB - To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.

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ER -

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

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