Biological, clinical and population relevance of 95 loci for blood lipids

TM Teslovich; K Musunuru; AV Smith; AC Edmondson; IM Stylianou; M Koseki; JP Pirruccello; S Ripatti; DI Chasman; CJ Willer; CT Johansen; SW Fouchier; Aaron Isaacs; GM Peloso; M Barbalic; SL Ricketts; JC Bis; YS Aulchenko; G Thorleifsson; MF Feitosa; J Chambers; M Orho-Melander; O Melander; T Johnson; XH Li; XQ Guo; MY Li; YS Cho; MJ Go; YJ Kim; JY Lee; T Park; K Kim; X Sim; RTH Ong; DC Croteau-Chonka; LA Lange; JD Smith; K Song; JH Zhao; X Yuan; JA Luan; C Lamina; A Ziegler; W Zhang; RYL Zee; AF Wright; JCM Witteman; JF Wilson; G Willemsen; HE Wichmann; JB Whitfield; DM Waterworth; NJ Wareham; G Waeber; P Vollenweider; BF Voight; V Vitart; André Uitterlinden; M Uda; J Tuomilehto; JR Thompson; T Tanaka; I Surakka; HM Stringham; TD Spector; N Soranzo; JH Smit; J Sinisalo; K Silander; E.J.G. Sijbrands; A Scuteri; J Scott; D Schlessinger; S Sanna; V Salomaa; J Saharinen; C Sabatti; A Ruokonen; I Rudan; LM Rose; R Roberts; M Rieder; BM Psaty; PP Pramstaller; I Pichler; M Perola; BWJH Penninx; NL Pedersen; C Pattaro; AN Parker; G Pare; Ben Oostra; CJ O'Donnell; MS Nieminen; DA Nickerson; GW Montgomery; T Meitinger; R McPherson; MI McCarthy; W McArdle; D Masson; NG Martin; F Marroni; M Mangino; PKE Magnusson; G Lucas; R Luben; RJF Loos; ML Lokki; G Lettre; C Langenberg; LJ (Lenore) Launer; EG Lakatta; R Laaksonen; KO Kyvik; F Kronenberg; IR Konig; KT Khaw; J Kaprio; LM Kaplan; A Johansson; MR Jarvelin; Cecile Janssens; E Ingelsson; W Igi; GK Hovingh; JJ (Jouke Jan) Hottenga; Bert Hofman; AA Hicks; C Hengstenberg; IM Heid; C Hayward; AS Havulinna; ND Hastie; TB Harris; T Haritunians; AS Hall; U Gyllensten; C Guiducci; LC Groop; E Gonzalez; C Gieger; NB Freimer; L Ferrucci; J Erdmann; P Elliott; KG Ejebe; A Doering; AF Dominiczak; S Demissie; P Deloukas; EJC de Geus; U de Faire; G Crawford; FS Collins; YDI Chen; MJ Caulfield; H Campbell; NP Burtt; LL Bonnycastle; DI Boomsma; SM Boekholdt; RN Bergman; I Barroso; S Bandinelli; CM Ballantyne; TL Assimes; T Quertermous; D Altshuler; M Seielstad; TY Wong; ES Tai; AB Feranil; CW Kuzawa; LS Adair; HA Taylor; IB Borecki; SB Gabriel; JG Wilson; H Holm; U Thorsteinsdottir; V Gudnason; RM Krauss; KL Mohlke; JM Ordovas; PB Munroe; JS Kooner; AR Tall; RA Hegele; JJP Kastelein; EE Schadt; JI Rotter; E Boerwinkle; DP Strachan; V Mooser; K Stefansson; MP Reilly; NJ Samani; H Schunkert; LA Cupples; MS Sandhu; PM Ridker; DJ Rader; Cornelia Duijn; L Peltonen; GR Abecasis; M Boehnke; S Kathiresan

doi:10.1038/nature09270

Biological, clinical and population relevance of 95 loci for blood lipids

TM Teslovich, K Musunuru, AV Smith, AC Edmondson, IM Stylianou, M Koseki, JP Pirruccello, S Ripatti, DI Chasman, CJ Willer, CT Johansen, SW Fouchier, Aaron Isaacs, GM Peloso, M Barbalic, SL Ricketts, JC Bis, YS Aulchenko, G Thorleifsson, MF FeitosaJ Chambers, M Orho-Melander, O Melander, T Johnson, XH Li, XQ Guo, MY Li, YS Cho, MJ Go, YJ Kim, JY Lee, T Park, K Kim, X Sim, RTH Ong, DC Croteau-Chonka, LA Lange, JD Smith, K Song, JH Zhao, X Yuan, JA Luan, C Lamina, A Ziegler, W Zhang, RYL Zee, AF Wright, JCM Witteman, JF Wilson, G Willemsen, HE Wichmann, JB Whitfield, DM Waterworth, NJ Wareham, G Waeber, P Vollenweider, BF Voight, V Vitart, André Uitterlinden, M Uda, J Tuomilehto, JR Thompson, T Tanaka, I Surakka, HM Stringham, TD Spector, N Soranzo, JH Smit, J Sinisalo, K Silander, E.J.G. Sijbrands, A Scuteri, J Scott, D Schlessinger, S Sanna, V Salomaa, J Saharinen, C Sabatti, A Ruokonen, I Rudan, LM Rose, R Roberts, M Rieder, BM Psaty, PP Pramstaller, I Pichler, M Perola, BWJH Penninx, NL Pedersen, C Pattaro, AN Parker, G Pare, Ben Oostra, CJ O'Donnell, MS Nieminen, DA Nickerson, GW Montgomery, T Meitinger, R McPherson, MI McCarthy, W McArdle, D Masson, NG Martin, F Marroni, M Mangino, PKE Magnusson, G Lucas, R Luben, RJF Loos, ML Lokki, G Lettre, C Langenberg, LJ (Lenore) Launer, EG Lakatta, R Laaksonen, KO Kyvik, F Kronenberg, IR Konig, KT Khaw, J Kaprio, LM Kaplan, A Johansson, MR Jarvelin, Cecile Janssens, E Ingelsson, W Igi, GK Hovingh, JJ (Jouke Jan) Hottenga, Bert Hofman, AA Hicks, C Hengstenberg, IM Heid, C Hayward, AS Havulinna, ND Hastie, TB Harris, T Haritunians, AS Hall, U Gyllensten, C Guiducci, LC Groop, E Gonzalez, C Gieger, NB Freimer, L Ferrucci, J Erdmann, P Elliott, KG Ejebe, A Doering, AF Dominiczak, S Demissie, P Deloukas, EJC de Geus, U de Faire, G Crawford, FS Collins, YDI Chen, MJ Caulfield, H Campbell, NP Burtt, LL Bonnycastle, DI Boomsma, SM Boekholdt, RN Bergman, I Barroso, S Bandinelli, CM Ballantyne, TL Assimes, T Quertermous, D Altshuler, M Seielstad, TY Wong, ES Tai, AB Feranil, CW Kuzawa, LS Adair, HA Taylor, IB Borecki, SB Gabriel, JG Wilson, H Holm, U Thorsteinsdottir, V Gudnason, RM Krauss, KL Mohlke, JM Ordovas, PB Munroe, JS Kooner, AR Tall, RA Hegele, JJP Kastelein, EE Schadt, JI Rotter, E Boerwinkle, DP Strachan, V Mooser, K Stefansson, MP Reilly, NJ Samani, H Schunkert, LA Cupples, MS Sandhu, PM Ridker, DJ Rader, Cornelia Duijn, L Peltonen, GR Abecasis, M Boehnke, S Kathiresan

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

3043 Citations (Scopus)

Abstract

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Original language	Undefined/Unknown
Pages (from-to)	707-713
Number of pages	7
Journal	Nature
Volume	466
Issue number	7307
DOIs	https://doi.org/10.1038/nature09270
Publication status	Published - 2010

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10.1038/nature09270

http://hdl.handle.net/1765/27283

Cite this

Teslovich, TM., Musunuru, K., Smith, AV., Edmondson, AC., Stylianou, IM., Koseki, M., Pirruccello, JP., Ripatti, S., Chasman, DI., Willer, CJ., Johansen, CT., Fouchier, SW., Isaacs, A., Peloso, GM., Barbalic, M., Ricketts, SL., Bis, JC., Aulchenko, YS., Thorleifsson, G., ... Kathiresan, S. (2010). Biological, clinical and population relevance of 95 loci for blood lipids. Nature, 466(7307), 707-713. https://doi.org/10.1038/nature09270

@article{862fedb547694bb39b0a32fb6f231fd1,

title = "Biological, clinical and population relevance of 95 loci for blood lipids",

abstract = "Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.",

author = "TM Teslovich and K Musunuru and AV Smith and AC Edmondson and IM Stylianou and M Koseki and JP Pirruccello and S Ripatti and DI Chasman and CJ Willer and CT Johansen and SW Fouchier and Aaron Isaacs and GM Peloso and M Barbalic and SL Ricketts and JC Bis and YS Aulchenko and G Thorleifsson and MF Feitosa and J Chambers and M Orho-Melander and O Melander and T Johnson and XH Li and XQ Guo and MY Li and YS Cho and MJ Go and YJ Kim and JY Lee and T Park and K Kim and X Sim and RTH Ong and DC Croteau-Chonka and LA Lange and JD Smith and K Song and JH Zhao and X Yuan and JA Luan and C Lamina and A Ziegler and W Zhang and RYL Zee and AF Wright and JCM Witteman and JF Wilson and G Willemsen and HE Wichmann and JB Whitfield and DM Waterworth and NJ Wareham and G Waeber and P Vollenweider and BF Voight and V Vitart and Andr{\'e} Uitterlinden and M Uda and J Tuomilehto and JR Thompson and T Tanaka and I Surakka and HM Stringham and TD Spector and N Soranzo and JH Smit and J Sinisalo and K Silander and E.J.G. Sijbrands and A Scuteri and J Scott and D Schlessinger and S Sanna and V Salomaa and J Saharinen and C Sabatti and A Ruokonen and I Rudan and LM Rose and R Roberts and M Rieder and BM Psaty and PP Pramstaller and I Pichler and M Perola and BWJH Penninx and NL Pedersen and C Pattaro and AN Parker and G Pare and Ben Oostra and CJ O'Donnell and MS Nieminen and DA Nickerson and GW Montgomery and T Meitinger and R McPherson and MI McCarthy and W McArdle and D Masson and NG Martin and F Marroni and M Mangino and PKE Magnusson and G Lucas and R Luben and RJF Loos and ML Lokki and G Lettre and C Langenberg and Launer, {LJ (Lenore)} and EG Lakatta and R Laaksonen and KO Kyvik and F Kronenberg and IR Konig and KT Khaw and J Kaprio and LM Kaplan and A Johansson and MR Jarvelin and Cecile Janssens and E Ingelsson and W Igi and GK Hovingh and Hottenga, {JJ (Jouke Jan)} and Bert Hofman and AA Hicks and C Hengstenberg and IM Heid and C Hayward and AS Havulinna and ND Hastie and TB Harris and T Haritunians and AS Hall and U Gyllensten and C Guiducci and LC Groop and E Gonzalez and C Gieger and NB Freimer and L Ferrucci and J Erdmann and P Elliott and KG Ejebe and A Doering and AF Dominiczak and S Demissie and P Deloukas and {de Geus}, EJC and {de Faire}, U and G Crawford and FS Collins and YDI Chen and MJ Caulfield and H Campbell and NP Burtt and LL Bonnycastle and DI Boomsma and SM Boekholdt and RN Bergman and I Barroso and S Bandinelli and CM Ballantyne and TL Assimes and T Quertermous and D Altshuler and M Seielstad and TY Wong and ES Tai and AB Feranil and CW Kuzawa and LS Adair and HA Taylor and IB Borecki and SB Gabriel and JG Wilson and H Holm and U Thorsteinsdottir and V Gudnason and RM Krauss and KL Mohlke and JM Ordovas and PB Munroe and JS Kooner and AR Tall and RA Hegele and JJP Kastelein and EE Schadt and JI Rotter and E Boerwinkle and DP Strachan and V Mooser and K Stefansson and MP Reilly and NJ Samani and H Schunkert and LA Cupples and MS Sandhu and PM Ridker and DJ Rader and Cornelia Duijn and L Peltonen and GR Abecasis and M Boehnke and S Kathiresan",

year = "2010",

doi = "10.1038/nature09270",

language = "Undefined/Unknown",

volume = "466",

pages = "707--713",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7307",

}

Teslovich, TM, Musunuru, K, Smith, AV, Edmondson, AC, Stylianou, IM, Koseki, M, Pirruccello, JP, Ripatti, S, Chasman, DI, Willer, CJ, Johansen, CT, Fouchier, SW, Isaacs, A, Peloso, GM, Barbalic, M, Ricketts, SL, Bis, JC, Aulchenko, YS, Thorleifsson, G, Feitosa, MF, Chambers, J, Orho-Melander, M, Melander, O, Johnson, T, Li, XH, Guo, XQ, Li, MY, Cho, YS, Go, MJ, Kim, YJ, Lee, JY, Park, T, Kim, K, Sim, X, Ong, RTH, Croteau-Chonka, DC, Lange, LA, Smith, JD, Song, K, Zhao, JH, Yuan, X, Luan, JA, Lamina, C, Ziegler, A, Zhang, W, Zee, RYL, Wright, AF, Witteman, JCM, Wilson, JF, Willemsen, G, Wichmann, HE, Whitfield, JB, Waterworth, DM, Wareham, NJ, Waeber, G, Vollenweider, P, Voight, BF, Vitart, V, Uitterlinden, A, Uda, M, Tuomilehto, J, Thompson, JR, Tanaka, T, Surakka, I, Stringham, HM, Spector, TD, Soranzo, N, Smit, JH, Sinisalo, J, Silander, K, Sijbrands, EJG, Scuteri, A, Scott, J, Schlessinger, D, Sanna, S, Salomaa, V, Saharinen, J, Sabatti, C, Ruokonen, A, Rudan, I, Rose, LM, Roberts, R, Rieder, M, Psaty, BM, Pramstaller, PP, Pichler, I, Perola, M, Penninx, BWJH, Pedersen, NL, Pattaro, C, Parker, AN, Pare, G, Oostra, B, O'Donnell, CJ, Nieminen, MS, Nickerson, DA, Montgomery, GW, Meitinger, T, McPherson, R, McCarthy, MI, McArdle, W, Masson, D, Martin, NG, Marroni, F, Mangino, M, Magnusson, PKE, Lucas, G, Luben, R, Loos, RJF, Lokki, ML, Lettre, G, Langenberg, C, Launer, LJ, Lakatta, EG, Laaksonen, R, Kyvik, KO, Kronenberg, F, Konig, IR, Khaw, KT, Kaprio, J, Kaplan, LM, Johansson, A, Jarvelin, MR, Janssens, C, Ingelsson, E, Igi, W, Hovingh, GK, Hottenga, JJ, Hofman, B, Hicks, AA, Hengstenberg, C, Heid, IM, Hayward, C, Havulinna, AS, Hastie, ND, Harris, TB, Haritunians, T, Hall, AS, Gyllensten, U, Guiducci, C, Groop, LC, Gonzalez, E, Gieger, C, Freimer, NB, Ferrucci, L, Erdmann, J, Elliott, P, Ejebe, KG, Doering, A, Dominiczak, AF, Demissie, S, Deloukas, P, de Geus, EJC, de Faire, U, Crawford, G, Collins, FS, Chen, YDI, Caulfield, MJ, Campbell, H, Burtt, NP, Bonnycastle, LL, Boomsma, DI, Boekholdt, SM, Bergman, RN, Barroso, I, Bandinelli, S, Ballantyne, CM, Assimes, TL, Quertermous, T, Altshuler, D, Seielstad, M, Wong, TY, Tai, ES, Feranil, AB, Kuzawa, CW, Adair, LS, Taylor, HA, Borecki, IB, Gabriel, SB, Wilson, JG, Holm, H, Thorsteinsdottir, U, Gudnason, V, Krauss, RM, Mohlke, KL, Ordovas, JM, Munroe, PB, Kooner, JS, Tall, AR, Hegele, RA, Kastelein, JJP, Schadt, EE, Rotter, JI, Boerwinkle, E, Strachan, DP, Mooser, V, Stefansson, K, Reilly, MP, Samani, NJ, Schunkert, H, Cupples, LA, Sandhu, MS, Ridker, PM, Rader, DJ, Duijn, C, Peltonen, L, Abecasis, GR, Boehnke, M & Kathiresan, S 2010, 'Biological, clinical and population relevance of 95 loci for blood lipids', Nature, vol. 466, no. 7307, pp. 707-713. https://doi.org/10.1038/nature09270

TY - JOUR

T1 - Biological, clinical and population relevance of 95 loci for blood lipids

AU - Teslovich, TM

AU - Musunuru, K

AU - Smith, AV

AU - Edmondson, AC

AU - Stylianou, IM

AU - Koseki, M

AU - Pirruccello, JP

AU - Ripatti, S

AU - Chasman, DI

AU - Willer, CJ

AU - Johansen, CT

AU - Fouchier, SW

AU - Isaacs, Aaron

AU - Peloso, GM

AU - Barbalic, M

AU - Ricketts, SL

AU - Bis, JC

AU - Aulchenko, YS

AU - Thorleifsson, G

AU - Feitosa, MF

AU - Chambers, J

AU - Orho-Melander, M

AU - Melander, O

AU - Johnson, T

AU - Li, XH

AU - Guo, XQ

AU - Li, MY

AU - Cho, YS

AU - Go, MJ

AU - Kim, YJ

AU - Lee, JY

AU - Park, T

AU - Kim, K

AU - Sim, X

AU - Ong, RTH

AU - Croteau-Chonka, DC

AU - Lange, LA

AU - Smith, JD

AU - Song, K

AU - Zhao, JH

AU - Yuan, X

AU - Luan, JA

AU - Lamina, C

AU - Ziegler, A

AU - Zhang, W

AU - Zee, RYL

AU - Wright, AF

AU - Witteman, JCM

AU - Wilson, JF

AU - Willemsen, G

AU - Wichmann, HE

AU - Whitfield, JB

AU - Waterworth, DM

AU - Wareham, NJ

AU - Waeber, G

AU - Vollenweider, P

AU - Voight, BF

AU - Vitart, V

AU - Uitterlinden, André

AU - Uda, M

AU - Tuomilehto, J

AU - Thompson, JR

AU - Tanaka, T

AU - Surakka, I

AU - Stringham, HM

AU - Spector, TD

AU - Soranzo, N

AU - Smit, JH

AU - Sinisalo, J

AU - Silander, K

AU - Sijbrands, E.J.G.

AU - Scuteri, A

AU - Scott, J

AU - Schlessinger, D

AU - Sanna, S

AU - Salomaa, V

AU - Saharinen, J

AU - Sabatti, C

AU - Ruokonen, A

AU - Rudan, I

AU - Rose, LM

AU - Roberts, R

AU - Rieder, M

AU - Psaty, BM

AU - Pramstaller, PP

AU - Pichler, I

AU - Perola, M

AU - Penninx, BWJH

AU - Pedersen, NL

AU - Pattaro, C

AU - Parker, AN

AU - Pare, G

AU - Oostra, Ben

AU - O'Donnell, CJ

AU - Nieminen, MS

AU - Nickerson, DA

AU - Montgomery, GW

AU - Meitinger, T

AU - McPherson, R

AU - McCarthy, MI

AU - McArdle, W

AU - Masson, D

AU - Martin, NG

AU - Marroni, F

AU - Mangino, M

AU - Magnusson, PKE

AU - Lucas, G

AU - Luben, R

AU - Loos, RJF

AU - Lokki, ML

AU - Lettre, G

AU - Langenberg, C

AU - Launer, LJ (Lenore)

AU - Lakatta, EG

AU - Laaksonen, R

AU - Kyvik, KO

AU - Kronenberg, F

AU - Konig, IR

AU - Khaw, KT

AU - Kaprio, J

AU - Kaplan, LM

AU - Johansson, A

AU - Jarvelin, MR

AU - Janssens, Cecile

AU - Ingelsson, E

AU - Igi, W

AU - Hovingh, GK

AU - Hottenga, JJ (Jouke Jan)

AU - Hofman, Bert

AU - Hicks, AA

AU - Hengstenberg, C

AU - Heid, IM

AU - Hayward, C

AU - Havulinna, AS

AU - Hastie, ND

AU - Harris, TB

AU - Haritunians, T

AU - Hall, AS

AU - Gyllensten, U

AU - Guiducci, C

AU - Groop, LC

AU - Gonzalez, E

AU - Gieger, C

AU - Freimer, NB

AU - Ferrucci, L

AU - Erdmann, J

AU - Elliott, P

AU - Ejebe, KG

AU - Doering, A

AU - Dominiczak, AF

AU - Demissie, S

AU - Deloukas, P

AU - de Geus, EJC

AU - de Faire, U

AU - Crawford, G

AU - Collins, FS

AU - Chen, YDI

AU - Caulfield, MJ

AU - Campbell, H

AU - Burtt, NP

AU - Bonnycastle, LL

AU - Boomsma, DI

AU - Boekholdt, SM

AU - Bergman, RN

AU - Barroso, I

AU - Bandinelli, S

AU - Ballantyne, CM

AU - Assimes, TL

AU - Quertermous, T

AU - Altshuler, D

AU - Seielstad, M

AU - Wong, TY

AU - Tai, ES

AU - Feranil, AB

AU - Kuzawa, CW

AU - Adair, LS

AU - Taylor, HA

AU - Borecki, IB

AU - Gabriel, SB

AU - Wilson, JG

AU - Holm, H

AU - Thorsteinsdottir, U

AU - Gudnason, V

AU - Krauss, RM

AU - Mohlke, KL

AU - Ordovas, JM

AU - Munroe, PB

AU - Kooner, JS

AU - Tall, AR

AU - Hegele, RA

AU - Kastelein, JJP

AU - Schadt, EE

AU - Rotter, JI

AU - Boerwinkle, E

AU - Strachan, DP

AU - Mooser, V

AU - Stefansson, K

AU - Reilly, MP

AU - Samani, NJ

AU - Schunkert, H

AU - Cupples, LA

AU - Sandhu, MS

AU - Ridker, PM

AU - Rader, DJ

AU - Duijn, Cornelia

AU - Peltonen, L

AU - Abecasis, GR

AU - Boehnke, M

AU - Kathiresan, S

PY - 2010

Y1 - 2010

N2 - Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

AB - Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P<5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

U2 - 10.1038/nature09270

DO - 10.1038/nature09270

M3 - Article

C2 - 20686565

SN - 0028-0836

VL - 466

SP - 707

EP - 713

JO - Nature

JF - Nature

IS - 7307

ER -