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 FriedrichCarsten 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, Reedik Magi, James Meigs, Dan Mellstrom, Matthias Nauck, Anne B. Newman, Michael N. Pollak, Peter P. Pramstaller, Inga Prokopenko, Bruce M. Psaty, Martin Reincke, Eric B. Rimm, Jerome I. Rotter, Aude Saint Pierre, Claudia Schurmann, Sudha Seshadri, Klara Sjogren, P. Eline Slagboom, Howard D. Strickler, Michael Stumvoll, Yousin Suh, Qi Sun, Cuilin Zhang, Johan Svensson, Toshiko Tanaka, Archana Tare, Anke Toenjes, Hae-Won Uh, Cornelia M. van Duijn, Diana van Heemst, Liesbeth Vandenput, Ramachandran S. Vasan, Uwe Voelker, Sara M. Willems, Claes Ohlsson, Henri Wallaschofski, Robert C. Kaplan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

59 Citations (Web of Science)

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. ? 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Original languageEnglish
Pages (from-to)811-824
JournalAging Cell
Volume15
Issue number5
DOIs
Publication statusPublished - Oct 2016

Keywords

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

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