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; 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 Oskari Kilpeläinen; Peter Kovacs; Peter Kraft; Chao Li; Allan Linneberg; Yongmei Liu; Ruth J F Loos; Mattias Lorentzon; Yingchang Lu; Marcello Maggio; CHARGE Longevity Working Group

doi:10.1111/acel.12490

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 Oskari Kilpeläinen, Peter Kovacs, Peter Kraft, Chao Li, Allan Linneberg, Yongmei Liu, Ruth J F Loos, Mattias Lorentzon, Yingchang Lu, Marcello Maggio, CHARGE Longevity Working Group

52 Citations (Scopus)

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 language	English
Article number	e1006166
Journal	Aging Cell
Volume	15
Issue number	5
Pages (from-to)	811-824
Number of pages	14
ISSN	1474-9718
DOIs	https://doi.org/10.1111/acel.12490
Publication status	Published - 1 Oct 2016

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Teumer, A., Qi, Q., Nethander, M., Aschard, H., Bandinelli, S., Beekman, M., Berndt, S. I., Bidlingmaier, M., Broer, L., Cappola, A., Ceda, G. P., Chanock, S., Chen, M.-H., Chen, T. C., Chen, Y.-D. I., Chung, J., Del Greco Miglianico, F., Eriksson, J., Ferrucci, L., ... CHARGE Longevity Working Group (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. Article e1006166. https://doi.org/10.1111/acel.12490

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, 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, Oskari Kilpeläinen, T, Kovacs, P, Kraft, P, Li, C, Linneberg, A, Liu, Y, Loos, RJF, Lorentzon, M, Lu, Y, Maggio, M & CHARGE Longevity Working Group 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, e1006166, pp. 811-824. https://doi.org/10.1111/acel.12490

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

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.",

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

note = "{\textcopyright} 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

year = "2016",

month = oct,

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doi = "10.1111/acel.12490",

language = "English",

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journal = "Aging Cell",

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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 - Oskari Kilpeläinen, Tuomas

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

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.

U2 - 10.1111/acel.12490

DO - 10.1111/acel.12490

M3 - Journal article

C2 - 27329260

SN - 1474-9718

VL - 15

SP - 811

EP - 824

JO - Aging Cell

JF - Aging Cell

IS - 5

M1 - e1006166

ER -

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

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