Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Alexander Teumer, Qibin Qi, Maria Nethander, Hugues Aschard, Stefania Bandinelli, Marian Beekman, Sonja I. Berndt, Martin Bidlingmaier, Linda Broer, Anne Cappola, Gian Paolo Ceda, Stephen Chanock, Ming Huei Chen, Tai C. Chen, Yii Der Ida Chen, Jonathan Chung, Fabiola Del Greco Miglianico, Joel Eriksson, Luigi Ferrucci, Nele Friedrich & 32 others Carsten Gnewuch, Mark O. Goodarzi, Niels Grarup, Tingwei Guo, Elke Hammer, Richard B. Hayes, Andrew A. Hicks, Albert Hofman, Jeanine J. Houwing-Duistermaat, Frank Hu, David J. Hunter, Lise L. Husemoen, Aaron Isaacs, Kevin B. Jacobs, Joop A M J L Janssen, John Olov Jansson, Nico Jehmlich, Simon Johnson, Anders Juul, Magnus Karlsson, Tuomas O. Kilpelainen, Peter Kovacs, Peter Kraft, Chao Li, Allan Linneberg, Yongmei Liu, Ruth J F Loos, Mattias Lorentzon, Yingchang Lu, Marcello Maggio, CHARGE Longevity Working Group, Body Composition Genetics Consortium

Research output: Contribution to journalArticle

Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Original languageEnglish (US)
Pages (from-to)811-824
Number of pages14
JournalAging Cell
Volume15
Issue number5
DOIs
StatePublished - Oct 1 2016
Externally publishedYes

Fingerprint

Insulin-Like Growth Factor Binding Protein 3
Insulin-Like Growth Factor I
Meta-Analysis
Single Nucleotide Polymorphism
Somatomedins
Adiposity
Computational Biology
Growth Hormone
Proteins
Cardiovascular Diseases
Animal Models
Alleles
Gene Expression
Survival
Genes

Keywords

  • aging
  • genomewide association study
  • growth hormone axis
  • IGF-I
  • IGFBP-3
  • longevity

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Teumer, A., Qi, Q., Nethander, M., Aschard, H., Bandinelli, S., Beekman, M., ... Body Composition Genetics Consortium (2016). Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell, 15(5), 811-824. https://doi.org/10.1111/acel.12490

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. / Teumer, Alexander; Qi, Qibin; Nethander, Maria; Aschard, Hugues; Bandinelli, Stefania; Beekman, Marian; Berndt, Sonja I.; Bidlingmaier, Martin; Broer, Linda; Cappola, Anne; Ceda, Gian Paolo; Chanock, Stephen; Chen, Ming Huei; Chen, Tai C.; Chen, Yii Der Ida; Chung, Jonathan; Del Greco Miglianico, Fabiola; Eriksson, Joel; Ferrucci, Luigi; Friedrich, Nele; Gnewuch, Carsten; Goodarzi, Mark O.; Grarup, Niels; Guo, Tingwei; Hammer, Elke; Hayes, Richard B.; Hicks, Andrew A.; Hofman, Albert; Houwing-Duistermaat, Jeanine J.; Hu, Frank; Hunter, David J.; Husemoen, Lise L.; Isaacs, Aaron; Jacobs, Kevin B.; Janssen, Joop A M J L; Jansson, John Olov; Jehmlich, Nico; Johnson, Simon; Juul, Anders; Karlsson, Magnus; Kilpelainen, Tuomas O.; Kovacs, Peter; Kraft, Peter; Li, Chao; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Lorentzon, Mattias; Lu, Yingchang; Maggio, Marcello; CHARGE Longevity Working Group; Body Composition Genetics Consortium.

In: Aging Cell, Vol. 15, No. 5, 01.10.2016, p. 811-824.

Research output: Contribution to journalArticle

Teumer, A, Qi, Q, Nethander, M, Aschard, H, Bandinelli, S, Beekman, M, Berndt, SI, Bidlingmaier, M, Broer, L, Cappola, A, Ceda, GP, Chanock, S, Chen, MH, Chen, TC, Chen, YDI, Chung, J, Del Greco Miglianico, F, Eriksson, J, Ferrucci, L, Friedrich, N, Gnewuch, C, Goodarzi, MO, Grarup, N, Guo, T, Hammer, E, Hayes, RB, Hicks, AA, Hofman, A, Houwing-Duistermaat, JJ, Hu, F, Hunter, DJ, Husemoen, LL, Isaacs, A, Jacobs, KB, Janssen, JAMJL, Jansson, JO, Jehmlich, N, Johnson, S, Juul, A, Karlsson, M, Kilpelainen, TO, Kovacs, P, Kraft, P, Li, C, Linneberg, A, Liu, Y, Loos, RJF, Lorentzon, M, Lu, Y, Maggio, M, CHARGE Longevity Working Group & Body Composition Genetics Consortium 2016, 'Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits', Aging Cell, vol. 15, no. 5, pp. 811-824. https://doi.org/10.1111/acel.12490
Teumer, Alexander ; Qi, Qibin ; Nethander, Maria ; Aschard, Hugues ; Bandinelli, Stefania ; Beekman, Marian ; Berndt, Sonja I. ; Bidlingmaier, Martin ; Broer, Linda ; Cappola, Anne ; Ceda, Gian Paolo ; Chanock, Stephen ; Chen, Ming Huei ; Chen, Tai C. ; Chen, Yii Der Ida ; Chung, Jonathan ; Del Greco Miglianico, Fabiola ; Eriksson, Joel ; Ferrucci, Luigi ; Friedrich, Nele ; Gnewuch, Carsten ; Goodarzi, Mark O. ; Grarup, Niels ; Guo, Tingwei ; Hammer, Elke ; Hayes, Richard B. ; Hicks, Andrew A. ; Hofman, Albert ; Houwing-Duistermaat, Jeanine J. ; Hu, Frank ; Hunter, David J. ; Husemoen, Lise L. ; Isaacs, Aaron ; Jacobs, Kevin B. ; Janssen, Joop A M J L ; Jansson, John Olov ; Jehmlich, Nico ; Johnson, Simon ; Juul, Anders ; Karlsson, Magnus ; Kilpelainen, Tuomas O. ; Kovacs, Peter ; Kraft, Peter ; Li, Chao ; Linneberg, Allan ; Liu, Yongmei ; Loos, Ruth J F ; Lorentzon, Mattias ; Lu, Yingchang ; Maggio, Marcello ; CHARGE Longevity Working Group ; Body Composition Genetics Consortium. / Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. In: Aging Cell. 2016 ; Vol. 15, No. 5. pp. 811-824.
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T1 - Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

AU - Teumer, Alexander

AU - Qi, Qibin

AU - Nethander, Maria

AU - Aschard, Hugues

AU - Bandinelli, Stefania

AU - Beekman, Marian

AU - Berndt, Sonja I.

AU - Bidlingmaier, Martin

AU - Broer, Linda

AU - Cappola, Anne

AU - Ceda, Gian Paolo

AU - Chanock, Stephen

AU - Chen, Ming Huei

AU - Chen, Tai C.

AU - Chen, Yii Der Ida

AU - Chung, Jonathan

AU - Del Greco Miglianico, Fabiola

AU - Eriksson, Joel

AU - Ferrucci, Luigi

AU - Friedrich, Nele

AU - Gnewuch, Carsten

AU - Goodarzi, Mark O.

AU - Grarup, Niels

AU - Guo, Tingwei

AU - Hammer, Elke

AU - Hayes, Richard B.

AU - Hicks, Andrew A.

AU - Hofman, Albert

AU - Houwing-Duistermaat, Jeanine J.

AU - Hu, Frank

AU - Hunter, David J.

AU - Husemoen, Lise L.

AU - Isaacs, Aaron

AU - Jacobs, Kevin B.

AU - Janssen, Joop A M J L

AU - Jansson, John Olov

AU - Jehmlich, Nico

AU - Johnson, Simon

AU - Juul, Anders

AU - Karlsson, Magnus

AU - Kilpelainen, Tuomas O.

AU - Kovacs, Peter

AU - Kraft, Peter

AU - Li, Chao

AU - Linneberg, Allan

AU - Liu, Yongmei

AU - Loos, Ruth J F

AU - Lorentzon, Mattias

AU - Lu, Yingchang

AU - Maggio, Marcello

AU - CHARGE Longevity Working Group

AU - Body Composition Genetics Consortium

PY - 2016/10/1

Y1 - 2016/10/1

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AB - The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype–phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

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KW - genomewide association study

KW - growth hormone axis

KW - IGF-I

KW - IGFBP-3

KW - longevity

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