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

Publication ,  Journal Article
Teumer, A; Qi, Q; Nethander, M; Aschard, H; Bandinelli, S; Beekman, M; Berndt, SI; Bidlingmaier, M; Broer, L; CHARGE Longevity Working Group, ...
Published in: Aging Cell
October 2016

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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Published In

Aging Cell

DOI

EISSN

1474-9726

Publication Date

October 2016

Volume

15

Issue

5

Start / End Page

811 / 824

Location

England

Related Subject Headings

  • Regulatory Sequences, Nucleic Acid
  • Quantitative Trait, Heritable
  • Quantitative Trait Loci
  • Metabolome
  • Male
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor Binding Protein 3
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation
 

Citation

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Teumer, A., Qi, Q., Nethander, M., Aschard, H., Bandinelli, S., Beekman, M., … Kaplan, R. C. (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
Teumer, Alexander, Qibin Qi, Maria Nethander, Hugues Aschard, Stefania Bandinelli, Marian Beekman, Sonja I. Berndt, et al. “Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.Aging Cell 15, no. 5 (October 2016): 811–24. https://doi.org/10.1111/acel.12490.
Teumer A, Qi Q, Nethander M, Aschard H, Bandinelli S, Beekman M, et al. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell. 2016 Oct;15(5):811–24.
Teumer, Alexander, et al. “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, Oct. 2016, pp. 811–24. Pubmed, doi:10.1111/acel.12490.
Teumer A, Qi Q, Nethander M, Aschard H, Bandinelli S, Beekman M, Berndt SI, Bidlingmaier M, Broer L, CHARGE Longevity Working Group, Cappola A, Ceda GP, Chanock S, Chen M-H, Chen TC, Chen Y-DI, 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 J-O, Jehmlich N, Johnson S, Juul A, Karlsson M, Kilpelainen TO, Kovacs P, Kraft P, Li C, Linneberg A, Liu Y, Loos RJF, Body Composition Genetics Consortium, Lorentzon M, Lu Y, Maggio M, Magi R, Meigs J, Mellström D, Nauck M, Newman AB, Pollak MN, Pramstaller PP, Prokopenko I, Psaty BM, Reincke M, Rimm EB, Rotter JI, Saint Pierre A, Schurmann C, Seshadri S, Sjögren K, Slagboom PE, Strickler HD, Stumvoll M, Suh Y, Sun Q, Zhang C, Svensson J, Tanaka T, Tare A, Tönjes A, Uh H-W, van Duijn CM, van Heemst D, Vandenput L, Vasan RS, Völker U, Willems SM, Ohlsson C, Wallaschofski H, Kaplan RC. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits. Aging Cell. 2016 Oct;15(5):811–824.
Journal cover image

Published In

Aging Cell

DOI

EISSN

1474-9726

Publication Date

October 2016

Volume

15

Issue

5

Start / End Page

811 / 824

Location

England

Related Subject Headings

  • Regulatory Sequences, Nucleic Acid
  • Quantitative Trait, Heritable
  • Quantitative Trait Loci
  • Metabolome
  • Male
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor Binding Protein 3
  • Humans
  • Genome-Wide Association Study
  • Gene Expression Regulation