Detection of genetic loci associated with plasma fetuin-A

A meta-analysis of genome-wide association studies from the CHARGE Consortium

Majken K. Jensen, Richard A. Jensen, Kenneth J. Mukamal, Xiuqing Guo, Jie Yao, Qi Sun, Marilyn Cornelis, Yongmei Liu, Ming Huei Chen, Jorge R. Kizer, Luc Djoussé, David S. Siscovick, Bruce M. Psaty, Joseph M. Zmuda, Jerome I. Rotter, Melissa Garcia, Tamara Harris, Ida Chen, Mark O. Goodarzi, Michael A. Nalls & 11 others Margaux Keller, Alice M. Arnold, Anne B. Newman, Ron C. Hoogeveen, Kathryn M. Rexrode, Eric B. Rimm, Frank B. Hu, Vasan S. Ramachandran, Ronit Katz, James S. Pankow, Joachim H. Ix

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3 Citations (Scopus)

Abstract

Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin- A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ~ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P=1.27×10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (~13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)2156-2163
Number of pages8
JournalHuman molecular genetics
Volume26
Issue number11
DOIs
StatePublished - Jan 1 2017

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alpha-2-HS-Glycoprotein
Genetic Loci
Genome-Wide Association Study
Meta-Analysis
Single Nucleotide Polymorphism
Genome
Genes
African Americans
Type 2 Diabetes Mellitus
Exons

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Detection of genetic loci associated with plasma fetuin-A : A meta-analysis of genome-wide association studies from the CHARGE Consortium. / Jensen, Majken K.; Jensen, Richard A.; Mukamal, Kenneth J.; Guo, Xiuqing; Yao, Jie; Sun, Qi; Cornelis, Marilyn; Liu, Yongmei; Chen, Ming Huei; Kizer, Jorge R.; Djoussé, Luc; Siscovick, David S.; Psaty, Bruce M.; Zmuda, Joseph M.; Rotter, Jerome I.; Garcia, Melissa; Harris, Tamara; Chen, Ida; Goodarzi, Mark O.; Nalls, Michael A.; Keller, Margaux; Arnold, Alice M.; Newman, Anne B.; Hoogeveen, Ron C.; Rexrode, Kathryn M.; Rimm, Eric B.; Hu, Frank B.; Ramachandran, Vasan S.; Katz, Ronit; Pankow, James S.; Ix, Joachim H.

In: Human molecular genetics, Vol. 26, No. 11, 01.01.2017, p. 2156-2163.

Research output: Contribution to journalArticle

Jensen, MK, Jensen, RA, Mukamal, KJ, Guo, X, Yao, J, Sun, Q, Cornelis, M, Liu, Y, Chen, MH, Kizer, JR, Djoussé, L, Siscovick, DS, Psaty, BM, Zmuda, JM, Rotter, JI, Garcia, M, Harris, T, Chen, I, Goodarzi, MO, Nalls, MA, Keller, M, Arnold, AM, Newman, AB, Hoogeveen, RC, Rexrode, KM, Rimm, EB, Hu, FB, Ramachandran, VS, Katz, R, Pankow, JS & Ix, JH 2017, 'Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium', Human molecular genetics, vol. 26, no. 11, pp. 2156-2163. https://doi.org/10.1093/hmg/ddx091
Jensen, Majken K. ; Jensen, Richard A. ; Mukamal, Kenneth J. ; Guo, Xiuqing ; Yao, Jie ; Sun, Qi ; Cornelis, Marilyn ; Liu, Yongmei ; Chen, Ming Huei ; Kizer, Jorge R. ; Djoussé, Luc ; Siscovick, David S. ; Psaty, Bruce M. ; Zmuda, Joseph M. ; Rotter, Jerome I. ; Garcia, Melissa ; Harris, Tamara ; Chen, Ida ; Goodarzi, Mark O. ; Nalls, Michael A. ; Keller, Margaux ; Arnold, Alice M. ; Newman, Anne B. ; Hoogeveen, Ron C. ; Rexrode, Kathryn M. ; Rimm, Eric B. ; Hu, Frank B. ; Ramachandran, Vasan S. ; Katz, Ronit ; Pankow, James S. ; Ix, Joachim H. / Detection of genetic loci associated with plasma fetuin-A : A meta-analysis of genome-wide association studies from the CHARGE Consortium. In: Human molecular genetics. 2017 ; Vol. 26, No. 11. pp. 2156-2163.
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title = "Detection of genetic loci associated with plasma fetuin-A: A meta-analysis of genome-wide association studies from the CHARGE Consortium",
abstract = "Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin- A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ~ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P=1.27×10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (~13{\%}) lower fetuin-A level. This variant alone explained 14{\%} of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.",
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T1 - Detection of genetic loci associated with plasma fetuin-A

T2 - A meta-analysis of genome-wide association studies from the CHARGE Consortium

AU - Jensen, Majken K.

AU - Jensen, Richard A.

AU - Mukamal, Kenneth J.

AU - Guo, Xiuqing

AU - Yao, Jie

AU - Sun, Qi

AU - Cornelis, Marilyn

AU - Liu, Yongmei

AU - Chen, Ming Huei

AU - Kizer, Jorge R.

AU - Djoussé, Luc

AU - Siscovick, David S.

AU - Psaty, Bruce M.

AU - Zmuda, Joseph M.

AU - Rotter, Jerome I.

AU - Garcia, Melissa

AU - Harris, Tamara

AU - Chen, Ida

AU - Goodarzi, Mark O.

AU - Nalls, Michael A.

AU - Keller, Margaux

AU - Arnold, Alice M.

AU - Newman, Anne B.

AU - Hoogeveen, Ron C.

AU - Rexrode, Kathryn M.

AU - Rimm, Eric B.

AU - Hu, Frank B.

AU - Ramachandran, Vasan S.

AU - Katz, Ronit

AU - Pankow, James S.

AU - Ix, Joachim H.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin- A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ~ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P=1.27×10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (~13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

AB - Plasma fetuin-A is associated with type 2 diabetes, and AHSG, the gene encoding fetuin-A, has been identified as a susceptibility locus for diabetes and metabolic syndrome. Thus far, unbiased investigations of the genetic determinants of plasma fetuin-A concentrations have not been conducted. We searched for single nucleotide polymorphisms (SNPs) related to fetuin- A concentrations by a genome-wide association study in six population-based studies. We examined the association of fetuin-A levels with ~ 2.5 million genotyped and imputed SNPs in 9,055 participants of European descent and 2,119 African Americans. In both ethnicities, the strongest associations were centered in a region with a high degree of LD near the AHSG locus. Among 136 genome-wide significant (P < 0.05 × 10-8) SNPs near the AHSG locus, the top SNP was rs4917 (P=1.27×10-303), a known coding SNP in exon 6 that is associated with a 0.06 g/l (~13%) lower fetuin-A level. This variant alone explained 14% of the variation in fetuin-A levels. Analyses conditioned on rs4917 indicated that the strong association with the AHSG locus stems from additional independent associations of multiple variants among European Americans. In conclusion, levels of fetuin-A in plasma are strongly associated with SNPs in its encoding gene, AHSG, but not elsewhere in the genome. Given the strength of the associations observed for multiple independent SNPs, the AHSG gene is an example of a candidate locus suitable for additional investigations including fine mapping to elucidate the biological basis of the findings and further functional experiments to clarify AHSG as a potential therapeutic target.

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