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

LifeLines Cohort Study; 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 Lyytikäinen; 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; Veronique Vitart; Caroline Hayward; James F Wilson

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

LifeLines Cohort Study, 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 VerweijEvangelos Evangelou, Leo-Pekka Lyytikäinen, 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, Veronique Vitart, Caroline Hayward, James F Wilson

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Abstract / Description of output

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

Original language	English
Journal	Journal of Medical Genetics
DOIs	https://doi.org/10.1136/jmedgenet-2015-103439
Publication status	Published - 1 Apr 2016

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10.1136/jmedgenet-2015-103439

Hayward C Meta-analysis of 49549 individuals
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LifeLines Cohort Study, 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., ... Wilson, J. F. (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. https://doi.org/10.1136/jmedgenet-2015-103439

@article{c4d9ee322bd4421f99b61f0a25f34ada,

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 = "BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.",

author = "{LifeLines Cohort Study} and {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 Lyytik{\"a}inen 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 Veronique Vitart and Caroline Hayward and Wilson, {James F}",

note = "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/",

year = "2016",

month = apr,

day = "1",

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

language = "English",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BRITISH MED JOURNAL PUBL GROUP",

}

LifeLines Cohort Study, 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, Lyytikäinen, 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 , Vitart, V , Hayward, C & Wilson, JF 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. 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 - LifeLines Cohort Study

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 - Lyytikäinen, 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 - Vitart, Veronique

AU - Hayward, Caroline

AU - Wilson, James F

N1 - 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/

PY - 2016/4/1

Y1 - 2016/4/1

N2 - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

AB - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

U2 - 10.1136/jmedgenet-2015-103439

DO - 10.1136/jmedgenet-2015-103439

M3 - Article

C2 - 27036123

SN - 0022-2593

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

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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