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 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 Mellström; 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 Sjögren; P Eline Slagboom; Howard D Strickler; Michael Stumvoll; Yousin Suh; Qi Sun; Cuilin Zhang; Johan Svensson; Toshiko Tanaka; Archana Tare; Anke Tönjes; Hae-Won Uh; Cornelia M van Duijn; Diana van Heemst; Liesbeth Vandenput; Ramachandran S Vasan; Uwe Völker; Sara M Willems; Claes Ohlsson; Henri Wallaschofski; Robert C Kaplan; CHARGE Longevity Working Group

doi:10.1111/acel.12490

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

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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, …

Aging cell, Vol.15(5), pp.811-824

10/2016

DOI: https://doi.org/10.1111/acel.12490

PMID: 27329260

Abstract

Adult

Aging - blood

Aging - genetics

Female

Gene Expression Regulation

Genome-Wide Association Study

Humans

Insulin-Like Growth Factor Binding Protein 3 - blood

Insulin-Like Growth Factor Binding Protein 3 - genetics

Insulin-Like Growth Factor I - genetics

Male

Metabolome - genetics

Quantitative Trait Loci - genetics

Quantitative Trait, Heritable

Regulatory Sequences, Nucleic Acid - genetics

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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Title: Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits
Creators: Alexander Teumer - Universitätsmedizin Greifswald
Qibin Qi - Albert Einstein College of Medicine
Maria Nethander - University of Gothenburg
Hugues Aschard - Harvard University
Stefania Bandinelli - Azienda Sanitaria di Firenze
Marian Beekman - Leiden University Medical Center
Sonja I Berndt - National Cancer Institute
Martin Bidlingmaier - LMU Klinikum
Linda Broer - Erasmus MC
Anne Cappola - University of Pennsylvania
Gian Paolo Ceda - University of Parma
Stephen Chanock - Universitätsmedizin Greifswald
Ming-Huei Chen - Boston University School of Medicine
Tai C Chen - Boston University
Yii-Der Ida Chen - The Lundquist Institute
Jonathan Chung - Albert Einstein College of Medicine
Fabiola Del Greco Miglianico - University of Lübeck
Joel Eriksson - University of Gothenburg
Luigi Ferrucci - National Institute on Aging
Nele Friedrich - Universitätsmedizin Greifswald
Carsten Gnewuch - Institute for Clinical Chemistry and Laboratory Medicine, Regensburg University Medical Center, D-93053, Regensburg, Germany
Mark O Goodarzi - Cedars-Sinai Medical Center
Niels Grarup - Novo Nordisk Foundation
Tingwei Guo - Albert Einstein College of Medicine
Elke Hammer - Universitätsmedizin Greifswald
Richard B Hayes - New York University
Andrew A Hicks - Eurac Research
Albert Hofman - Erasmus MC
Jeanine J Houwing-Duistermaat - Leiden University Medical Center
Frank Hu - Harvard University
David J Hunter - Harvard University
Lise L Husemoen - Capital Region of Denmark
Aaron Isaacs - Centre for Medical Systems Biology
Kevin B Jacobs - Universitätsmedizin Greifswald
Joop A M J L Janssen - Erasmus MC
John-Olov Jansson - University of Gothenburg
Nico Jehmlich - Universitätsmedizin Greifswald
Simon Johnson - Albert Einstein College of Medicine
Anders Juul - University of Copenhagen
Magnus Karlsson - Lund University
Tuomas O Kilpelainen - University of Copenhagen
Peter Kovacs - IFB Adiposity Diseases
Peter Kraft - Brigham and Women's Hospital
Chao Li - Albert Einstein College of Medicine
Allan Linneberg - Capital Region of Denmark
Yongmei Liu - Wake Forest University
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Mattias Lorentzon - University of Gothenburg
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Marcello Maggio - University of Parma
Reedik Magi - University of Tartu
James Meigs - Massachusetts General Hospital
Dan Mellström - University of Gothenburg
Matthias Nauck - Harvard University
Anne B Newman - University of Pittsburgh
Michael N Pollak - McGill University
Peter P Pramstaller - Eurac Research
Inga Prokopenko - Imperial College London
Bruce M Psaty - University of Washington
Martin Reincke - LMU Klinikum
Eric B Rimm - Harvard University
Jerome I Rotter - The Lundquist Institute
Aude Saint Pierre - Inserm
Claudia Schurmann - Icahn School of Medicine at Mount Sinai
Sudha Seshadri - Boston University
Klara Sjögren - University of Gothenburg
P Eline Slagboom - Leiden University Medical Center
Howard D Strickler - Albert Einstein College of Medicine
Michael Stumvoll - IFB Adiposity Diseases
Yousin Suh - Albert Einstein College of Medicine
Qi Sun - Harvard University
Cuilin Zhang - Eunice Kennedy Shriver National Institute of Child Health and Human Development
Johan Svensson - University of Gothenburg
Toshiko Tanaka - National Institute on Aging
Archana Tare - Albert Einstein College of Medicine
Anke Tönjes - Leipzig University
Hae-Won Uh - Leiden University Medical Center
Cornelia M van Duijn - Centre for Medical Systems Biology
Diana van Heemst - Leiden University Medical Center
Liesbeth Vandenput - University of Gothenburg
Ramachandran S Vasan - Boston University
Uwe Völker - Universitätsmedizin Greifswald
Sara M Willems - University Hospital and Clinics
Claes Ohlsson - University of Gothenburg
Henri Wallaschofski - Universitätsmedizin Greifswald
Robert C Kaplan - Albert Einstein College of Medicine
CHARGE Longevity Working Group
Publication Details: Aging cell, Vol.15(5), pp.811-824
Date published: 10/2016
Grant note: P30 AG024827 / NIA NIH HHS HHSN268201200036C / NHLBI NIH HHS K24 DK080140 / NIDDK NIH HHS HHSN268200800007C / NHLBI NIH HHS U01 DK078616 / NIDDK NIH HHS N01HC85082 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS UL1 TR001881 / NCATS NIH HHS R01 HL105756 / NHLBI NIH HHS R01 AG023629 / NIA NIH HHS
Identifiers: 99929057402346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article

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

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