TY - JOUR
T1 - Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits
AU - Body Composition Genetics Consortium
AU - CHARGE Longevity Working Group
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 - Strickler, Howard D.
AU - Suh, Yousin
AU - Kaplan, Robert C.
N1 - Publisher Copyright:
© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
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.
KW - IGF-I
KW - IGFBP-3
KW - aging
KW - genomewide association study
KW - growth hormone axis
KW - longevity
UR - http://www.scopus.com/inward/record.url?scp=84986232247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84986232247&partnerID=8YFLogxK
U2 - 10.1111/acel.12490
DO - 10.1111/acel.12490
M3 - Article
C2 - 27329260
AN - SCOPUS:84986232247
SN - 1474-9718
VL - 15
SP - 811
EP - 824
JO - Aging cell
JF - Aging cell
IS - 5
ER -
