Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Elisabeth M. van Leeuwen; Aniko Sabo; Joshua C. Bis; Jennifer E. Huffman; Ani Manichaikul; Albert V. Smith; Mary F. Feitosa; Serkalem Demissie; Peter K. Joshi; Qing Duan; Jonathan Marten; Jan B. van Klinken; Ida Surakka; Ilja M. Nolte; Weihua Zhang; Hamdi Mbarek; Ruifang Li-Gao; Stella Trompet; Niek Verweij; Evangelos Evangelou; Leo-Pekka Lyytikainen; Bamidele O. Tayo; Joris Deelen; Peter J. van der Most; Sander W. van der Laan; Dan E. Arking; Alanna Morrison; Abbas Dehghan; Oscar H. Franco; Albert Hofman; Fernando Rivadeneira; Eric J. Sijbrands; Andre G. Uitterlinden; Josyf C. Mychaleckyj; Archie Campbell; Lynne J. Hocking; Sandosh Padmanabhan; Jennifer A. Brody; Kenneth M. Rice; Charles C. White; Tamara Harris; Aaron Isaacs; Harry Campbell; Leslie A. Lange; Igor Rudan; Ivana Kolcic; Pau Navarro; Tatijana Zemunik; Veikko Salomaa; Angad S. Kooner; Jaspal S. Kooner; Benjamin Lehne; William R. Scott; Sian-Tsung Tan; Eco J. de Geus; Yuri Milaneschi; Brenda W. J. H. Penninx; Gonneke Willemsen; Renee de Mutsert; Ian Ford; Ron T. Gansevoort; Marcelo P. Segura-Lepe; Olli T. Raitakari; Jorma S. Viikari; Kjell Nikus; Terrence Forrester; Colin A. McKenzie; Anton J. M. de Craen; Hester M. de Ruijter; Gerard Pasterkamp; Harold Snieder; Albertine J. Oldehinkel; P. Eline Slagboom; Richard S. Cooper; Mika Kahonen; Terho Lehtimaki; Paul Elliott; Pim van der Harst; J. Wouter Jukema; Dennis O. Mook-Kanamori; Dorret I. Boomsma; John C. Chambers; Morris Swertz; Samuli Ripatti; Ko Willems van Dijk; Veronique Vitart; Ozren Polasek; Caroline Hayward; James G. Wilson; James F. Wilson; Vilmundur Gudnason; Stephen S. Rich; Bruce M. Psaty; Ingrid B. Borecki; Eric Boerwinkle; Jerome I. Rotter; L. Adrienne Cupples; Cornelia M. van Duijn

doi:10.1136/jmedgenet-2015-103439

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Elisabeth M. van Leeuwen, Aniko Sabo, Joshua C. Bis, Jennifer E. Huffman, Ani Manichaikul, Albert V. Smith, Mary F. Feitosa, Serkalem Demissie, Peter K. Joshi, Qing Duan, Jonathan Marten, Jan B. van Klinken, Ida Surakka, Ilja M. Nolte, Weihua Zhang, Hamdi Mbarek, Ruifang Li-Gao, Stella Trompet, Niek Verweij, Evangelos EvangelouLeo-Pekka Lyytikainen, Bamidele O. Tayo, Joris Deelen, Peter J. van der Most, Sander W. van der Laan, Dan E. Arking, Alanna Morrison, Abbas Dehghan, Oscar H. Franco, Albert Hofman, Fernando Rivadeneira, Eric J. Sijbrands, Andre G. Uitterlinden, Josyf C. Mychaleckyj, Archie Campbell, Lynne J. Hocking, Sandosh Padmanabhan, Jennifer A. Brody, Kenneth M. Rice, Charles C. White, Tamara Harris, Aaron Isaacs, Harry Campbell, Leslie A. Lange, Igor Rudan, Ivana Kolcic, Pau Navarro, Tatijana Zemunik, Veikko Salomaa, Angad S. Kooner, Jaspal S. Kooner, Benjamin Lehne, William R. Scott, Sian-Tsung Tan, Eco J. de Geus, Yuri Milaneschi, Brenda W. J. H. Penninx, Gonneke Willemsen, Renee de Mutsert, Ian Ford, Ron T. Gansevoort, Marcelo P. Segura-Lepe, Olli T. Raitakari, Jorma S. Viikari, Kjell Nikus, Terrence Forrester, Colin A. McKenzie, Anton J. M. de Craen, Hester M. de Ruijter, Gerard Pasterkamp, Harold Snieder, Albertine J. Oldehinkel, P. Eline Slagboom, Richard S. Cooper, Mika Kahonen, Terho Lehtimaki, Paul Elliott, Pim van der Harst, J. Wouter Jukema, Dennis O. Mook-Kanamori, Dorret I. Boomsma, John C. Chambers, Morris Swertz, Samuli Ripatti, Ko Willems van Dijk, Veronique Vitart, Ozren Polasek, Caroline Hayward, James G. Wilson, James F. Wilson, Vilmundur Gudnason, Stephen S. Rich, Bruce M. Psaty, Ingrid B. Borecki, Eric Boerwinkle, Jerome I. Rotter, L. Adrienne Cupples, Cornelia M. van Duijn^*

^*Corresponding author for this work

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

Abstract

So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ?60?000 individuals in the discovery stage and ?90?000 samples in the replication stage.Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Original language	English
Pages (from-to)	441-449
Journal	Journal of Medical Genetics
Volume	53
Issue number	7
DOIs	https://doi.org/10.1136/jmedgenet-2015-103439
Publication status	Published - Jul 2016

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van Leeuwen, E. M., Sabo, A., Bis, J. C., Huffman, J. E., Manichaikul, A., Smith, A. V., Feitosa, M. F., Demissie, S., Joshi, P. K., Duan, Q., Marten, J., van Klinken, J. B., Surakka, I., Nolte, I. M., Zhang, W., Mbarek, H., Li-Gao, R., Trompet, S., Verweij, N., ... van Duijn, C. M. (2016). Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels. Journal of Medical Genetics, 53(7), 441-449. https://doi.org/10.1136/jmedgenet-2015-103439

@article{1a181ea221d24e85ba774709a4410696,

title = "Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels",

abstract = "So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ?60?000 individuals in the discovery stage and ?90?000 samples in the replication stage.Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/",

author = "{van Leeuwen}, {Elisabeth M.} and Aniko Sabo and Bis, {Joshua C.} and Huffman, {Jennifer E.} and Ani Manichaikul and Smith, {Albert V.} and Feitosa, {Mary F.} and Serkalem Demissie and Joshi, {Peter K.} and Qing Duan and Jonathan Marten and {van Klinken}, {Jan B.} and Ida Surakka and Nolte, {Ilja M.} and Weihua Zhang and Hamdi Mbarek and Ruifang Li-Gao and Stella Trompet and Niek Verweij and Evangelos Evangelou and Leo-Pekka Lyytikainen and Tayo, {Bamidele O.} and Joris Deelen and {van der Most}, {Peter J.} and {van der Laan}, {Sander W.} and Arking, {Dan E.} and Alanna Morrison and Abbas Dehghan and Franco, {Oscar H.} and Albert Hofman and Fernando Rivadeneira and Sijbrands, {Eric J.} and Uitterlinden, {Andre G.} and Mychaleckyj, {Josyf C.} and Archie Campbell and Hocking, {Lynne J.} and Sandosh Padmanabhan and Brody, {Jennifer A.} and Rice, {Kenneth M.} and White, {Charles C.} and Tamara Harris and Aaron Isaacs and Harry Campbell and Lange, {Leslie A.} and Igor Rudan and Ivana Kolcic and Pau Navarro and Tatijana Zemunik and Veikko Salomaa and Kooner, {Angad S.} and Kooner, {Jaspal S.} and Benjamin Lehne and Scott, {William R.} and Sian-Tsung Tan and {de Geus}, {Eco J.} and Yuri Milaneschi and Penninx, {Brenda W. J. H.} and Gonneke Willemsen and {de Mutsert}, Renee and Ian Ford and Gansevoort, {Ron T.} and Segura-Lepe, {Marcelo P.} and Raitakari, {Olli T.} and Viikari, {Jorma S.} and Kjell Nikus and Terrence Forrester and McKenzie, {Colin A.} and {de Craen}, {Anton J. M.} and {de Ruijter}, {Hester M.} and Gerard Pasterkamp and Harold Snieder and Oldehinkel, {Albertine J.} and Slagboom, {P. Eline} and Cooper, {Richard S.} and Mika Kahonen and Terho Lehtimaki and Paul Elliott and {van der Harst}, Pim and Jukema, {J. Wouter} and Mook-Kanamori, {Dennis O.} and Boomsma, {Dorret I.} and Chambers, {John C.} and Morris Swertz and Samuli Ripatti and {van Dijk}, {Ko Willems} and Veronique Vitart and Ozren Polasek and Caroline Hayward and Wilson, {James G.} and Wilson, {James F.} and Vilmundur Gudnason and Rich, {Stephen S.} and Psaty, {Bruce M.} and Borecki, {Ingrid B.} and Eric Boerwinkle and Rotter, {Jerome I.} and Cupples, {L. Adrienne} and {van Duijn}, {Cornelia M.}",

year = "2016",

month = jul,

doi = "10.1136/jmedgenet-2015-103439",

language = "English",

volume = "53",

pages = "441--449",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "7",

}

van Leeuwen, EM, Sabo, A, Bis, JC, Huffman, JE, Manichaikul, A, Smith, AV, Feitosa, MF, Demissie, S, Joshi, PK, Duan, Q, Marten, J, van Klinken, JB, Surakka, I, Nolte, IM, Zhang, W, Mbarek, H, Li-Gao, R, Trompet, S, Verweij, N, Evangelou, E, Lyytikainen, L-P, Tayo, BO, Deelen, J, van der Most, PJ, van der Laan, SW, Arking, DE, Morrison, A, Dehghan, A, Franco, OH, Hofman, A, Rivadeneira, F, Sijbrands, EJ, Uitterlinden, AG, Mychaleckyj, JC, Campbell, A, Hocking, LJ, Padmanabhan, S, Brody, JA, Rice, KM, White, CC, Harris, T, Isaacs, A, Campbell, H, Lange, LA, Rudan, I, Kolcic, I, Navarro, P, Zemunik, T, Salomaa, V, Kooner, AS, Kooner, JS, Lehne, B, Scott, WR, Tan, S-T, de Geus, EJ, Milaneschi, Y, Penninx, BWJH, Willemsen, G, de Mutsert, R, Ford, I, Gansevoort, RT, Segura-Lepe, MP, Raitakari, OT, Viikari, JS, Nikus, K, Forrester, T, McKenzie, CA, de Craen, AJM, de Ruijter, HM, Pasterkamp, G, Snieder, H, Oldehinkel, AJ, Slagboom, PE, Cooper, RS, Kahonen, M, Lehtimaki, T, Elliott, P, van der Harst, P, Jukema, JW, Mook-Kanamori, DO, Boomsma, DI, Chambers, JC, Swertz, M, Ripatti, S, van Dijk, KW, Vitart, V, Polasek, O, Hayward, C, Wilson, JG, Wilson, JF, Gudnason, V, Rich, SS, Psaty, BM, Borecki, IB, Boerwinkle, E, Rotter, JI, Cupples, LA & van Duijn, CM 2016, 'Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels', Journal of Medical Genetics, vol. 53, no. 7, pp. 441-449. https://doi.org/10.1136/jmedgenet-2015-103439

TY - JOUR

T1 - Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

AU - van Leeuwen, Elisabeth M.

AU - Sabo, Aniko

AU - Bis, Joshua C.

AU - Huffman, Jennifer E.

AU - Manichaikul, Ani

AU - Smith, Albert V.

AU - Feitosa, Mary F.

AU - Demissie, Serkalem

AU - Joshi, Peter K.

AU - Duan, Qing

AU - Marten, Jonathan

AU - van Klinken, Jan B.

AU - Surakka, Ida

AU - Nolte, Ilja M.

AU - Zhang, Weihua

AU - Mbarek, Hamdi

AU - Li-Gao, Ruifang

AU - Trompet, Stella

AU - Verweij, Niek

AU - Evangelou, Evangelos

AU - Lyytikainen, Leo-Pekka

AU - Tayo, Bamidele O.

AU - Deelen, Joris

AU - van der Most, Peter J.

AU - van der Laan, Sander W.

AU - Arking, Dan E.

AU - Morrison, Alanna

AU - Dehghan, Abbas

AU - Franco, Oscar H.

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Sijbrands, Eric J.

AU - Uitterlinden, Andre G.

AU - Mychaleckyj, Josyf C.

AU - Campbell, Archie

AU - Hocking, Lynne J.

AU - Padmanabhan, Sandosh

AU - Brody, Jennifer A.

AU - Rice, Kenneth M.

AU - White, Charles C.

AU - Harris, Tamara

AU - Isaacs, Aaron

AU - Campbell, Harry

AU - Lange, Leslie A.

AU - Rudan, Igor

AU - Kolcic, Ivana

AU - Navarro, Pau

AU - Zemunik, Tatijana

AU - Salomaa, Veikko

AU - Kooner, Angad S.

AU - Kooner, Jaspal S.

AU - Lehne, Benjamin

AU - Scott, William R.

AU - Tan, Sian-Tsung

AU - de Geus, Eco J.

AU - Milaneschi, Yuri

AU - Penninx, Brenda W. J. H.

AU - Willemsen, Gonneke

AU - de Mutsert, Renee

AU - Ford, Ian

AU - Gansevoort, Ron T.

AU - Segura-Lepe, Marcelo P.

AU - Raitakari, Olli T.

AU - Viikari, Jorma S.

AU - Nikus, Kjell

AU - Forrester, Terrence

AU - McKenzie, Colin A.

AU - de Craen, Anton J. M.

AU - de Ruijter, Hester M.

AU - Pasterkamp, Gerard

AU - Snieder, Harold

AU - Oldehinkel, Albertine J.

AU - Slagboom, P. Eline

AU - Cooper, Richard S.

AU - Kahonen, Mika

AU - Lehtimaki, Terho

AU - Elliott, Paul

AU - van der Harst, Pim

AU - Jukema, J. Wouter

AU - Mook-Kanamori, Dennis O.

AU - Boomsma, Dorret I.

AU - Chambers, John C.

AU - Swertz, Morris

AU - Ripatti, Samuli

AU - van Dijk, Ko Willems

AU - Vitart, Veronique

AU - Polasek, Ozren

AU - Hayward, Caroline

AU - Wilson, James G.

AU - Wilson, James F.

AU - Gudnason, Vilmundur

AU - Rich, Stephen S.

AU - Psaty, Bruce M.

AU - Borecki, Ingrid B.

AU - Boerwinkle, Eric

AU - Rotter, Jerome I.

AU - Cupples, L. Adrienne

AU - van Duijn, Cornelia M.

PY - 2016/7

Y1 - 2016/7

N2 - So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ?60?000 individuals in the discovery stage and ?90?000 samples in the replication stage.Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

AB - So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ?60?000 individuals in the discovery stage and ?90?000 samples in the replication stage.Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

U2 - 10.1136/jmedgenet-2015-103439

DO - 10.1136/jmedgenet-2015-103439

M3 - Article

C2 - 27036123

SN - 0022-2593

VL - 53

SP - 441

EP - 449

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 7

ER -

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

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