Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations

Rita P. Middelberg; Beben Benyamin; Marleen H.M. de Moor; Nicole M. Warrington; Scott Gordon; Anjali K. Henders; Sarah E. Medland; Dale R. Nyholt; Eco J.C. de Geus; Jouke J. Hottenga; Gonneke Willemsen; Lawrence J. Beilin; Trevor A. Mori; Margaret J. Wright; Andrew C. Heath; Pamela A.F. Madden; Dorret I. Boomsma; Craig E. Pennell; Grant W. Montgomery; Nicholas G. Martin; John B. Whitfield

doi:10.1093/hmg/ddr478

Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations

Rita P. Middelberg
, Beben Benyamin
, Marleen H.M. de Moor
, Nicole M. Warrington
, Scott Gordon
, Anjali K. Henders
, Sarah E. Medland
, Dale R. Nyholt
, Eco J.C. de Geus
, Jouke J. Hottenga
, Gonneke Willemsen
, Lawrence J. Beilin
, Trevor A. Mori
, Margaret J. Wright
, Andrew C. Heath
, Pamela A.F. Madden
, Dorret I. Boomsma
, Craig E. Pennell
, Grant W. Montgomery
, Nicholas G. Martin

John B. Whitfield^*

^*Corresponding author for this work

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

26 Citations (Scopus)

Abstract

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10 ^-8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10 ^-13; rs340005 in RORA on chromosome 15, P = 2.4 × 10 ^-8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P _HET = 5.6 × 10 ^-12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

Original language	English
Article number	ddr478
Pages (from-to)	446-455
Number of pages	10
Journal	Human Molecular Genetics
Volume	21
Issue number	2
DOIs	https://doi.org/10.1093/hmg/ddr478
Publication status	Published - Jan 2012
Externally published	Yes

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Middelberg, R. P., Benyamin, B., de Moor, M. H. M., Warrington, N. M., Gordon, S., Henders, A. K., Medland, S. E., Nyholt, D. R., de Geus, E. J. C., Hottenga, J. J., Willemsen, G., Beilin, L. J., Mori, T. A., Wright, M. J., Heath, A. C., Madden, P. A. F., Boomsma, D. I., Pennell, C. E., Montgomery, G. W., ... Whitfield, J. B. (2012). Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations. Human Molecular Genetics, 21(2), 446-455. Article ddr478. https://doi.org/10.1093/hmg/ddr478

@article{c71f0896a9bc4d46933f024662330801,

title = "Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations",

abstract = "Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10 -8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10 -13; rs340005 in RORA on chromosome 15, P = 2.4 × 10 -8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P HET = 5.6 × 10 -12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.",

author = "Middelberg, \{Rita P.\} and Beben Benyamin and \{de Moor\}, \{Marleen H.M.\} and Warrington, \{Nicole M.\} and Scott Gordon and Henders, \{Anjali K.\} and Medland, \{Sarah E.\} and Nyholt, \{Dale R.\} and \{de Geus\}, \{Eco J.C.\} and Hottenga, \{Jouke J.\} and Gonneke Willemsen and Beilin, \{Lawrence J.\} and Mori, \{Trevor A.\} and Wright, \{Margaret J.\} and Heath, \{Andrew C.\} and Madden, \{Pamela A.F.\} and Boomsma, \{Dorret I.\} and Pennell, \{Craig E.\} and Montgomery, \{Grant W.\} and Martin, \{Nicholas G.\} and Whitfield, \{John B.\}",

year = "2012",

month = jan,

doi = "10.1093/hmg/ddr478",

language = "English",

volume = "21",

pages = "446--455",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "2",

}

Middelberg, RP, Benyamin, B, de Moor, MHM, Warrington, NM, Gordon, S, Henders, AK, Medland, SE, Nyholt, DR, de Geus, EJC, Hottenga, JJ, Willemsen, G, Beilin, LJ, Mori, TA, Wright, MJ, Heath, AC, Madden, PAF, Boomsma, DI, Pennell, CE, Montgomery, GW, Martin, NG & Whitfield, JB 2012, 'Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations', Human Molecular Genetics, vol. 21, no. 2, ddr478, pp. 446-455. https://doi.org/10.1093/hmg/ddr478

TY - JOUR

T1 - Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations

AU - Middelberg, Rita P.

AU - Benyamin, Beben

AU - de Moor, Marleen H.M.

AU - Warrington, Nicole M.

AU - Gordon, Scott

AU - Henders, Anjali K.

AU - Medland, Sarah E.

AU - Nyholt, Dale R.

AU - de Geus, Eco J.C.

AU - Hottenga, Jouke J.

AU - Willemsen, Gonneke

AU - Beilin, Lawrence J.

AU - Mori, Trevor A.

AU - Wright, Margaret J.

AU - Heath, Andrew C.

AU - Madden, Pamela A.F.

AU - Boomsma, Dorret I.

AU - Pennell, Craig E.

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Whitfield, John B.

PY - 2012/1

Y1 - 2012/1

N2 - Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10 -8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10 -13; rs340005 in RORA on chromosome 15, P = 2.4 × 10 -8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P HET = 5.6 × 10 -12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

AB - Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in an intergenic region of chromosome 1, P = 3.9 × 10 -8; rs944002 in C14orf73 on chromosome 14, P = 4.7 × 10 -13; rs340005 in RORA on chromosome 15, P = 2.4 × 10 -8), and a highly significant heterogeneity between adult and adolescent results at the GGT1 locus on chromosome 22 (maximum P HET = 5.6 × 10 -12 at rs6519520). Pathway analysis of significant and suggestive single-nucleotide polymorphism associations showed significant overlap between genes affecting GGT and those affecting common metabolic and inflammatory diseases, and identified the hepatic nuclear factor (HNF) family as controllers of a network of genes affecting GGT. Our results reinforce the disease associations of GGT and demonstrate that control by the GGT1 locus varies with age.

UR - https://www.scopus.com/pages/publications/84855369567

U2 - 10.1093/hmg/ddr478

DO - 10.1093/hmg/ddr478

M3 - Article

C2 - 22010049

AN - SCOPUS:84855369567

SN - 0964-6906

VL - 21

SP - 446

EP - 455

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

M1 - ddr478

ER -

Loci affecting gamma-glutamyl transferase in adults and adolescents show age × SNP interaction and cardiometabolic disease associations

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