Open AccessGenomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits
Author(s) -
Teumer Alexander,
Qi Qibin,
Nethander Maria,
Aschard Hugues,
Bandinelli Stefania,
Beekman Marian,
Berndt Sonja I.,
Bidlingmaier Martin,
Broer Linda,
Cappola Anne,
Ceda Gian Paolo,
Chanock Stephen,
Chen MingHuei,
Chen Tai C.,
Chen YiiDer Ida,
Chung Jonathan,
Del Greco Miglianico Fabiola,
Eriksson Joel,
Ferrucci Luigi,
Friedrich Nele,
Gnewuch Carsten,
Goodarzi Mark O.,
Grarup Niels,
Guo Tingwei,
Hammer Elke,
Hayes Richard B.,
Hicks Andrew A.,
Hofman Albert,
HouwingDuistermaat Jeanine J.,
Hu Frank,
Hunter David J.,
Husemoen Lise L.,
Isaacs Aaron,
Jacobs Kevin B.,
Janssen Joop A. M. J. L.,
Jansson JohnOlov,
Jehmlich Nico,
Johnson Simon,
Juul Anders,
Karlsson Magnus,
Kilpelainen Tuomas O.,
Kovacs Peter,
Kraft Peter,
Li Chao,
Linneberg Allan,
Liu Yongmei,
Loos Ruth J. F.,
Lorentzon Mattias,
Lu Yingchang,
Maggio Marcello,
Magi Reedik,
Meigs James,
Mellström Dan,
Nauck Matthias,
Newman Anne B.,
Pollak Michael N.,
Pramstaller Peter P.,
Prokopenko Inga,
Psaty Bruce M.,
Reincke Martin,
Rimm Eric B.,
Rotter Jerome I.,
Saint Pierre Aude,
Schurmann Claudia,
Seshadri Sudha,
Sjögren Klara,
Slagboom P. Eline,
Strickler Howard D.,
Stumvoll Michael,
Suh Yousin,
Sun Qi,
Zhang Cuilin,
Svensson Johan,
Tanaka Toshiko,
Tare Archana,
Tönjes Anke,
Uh HaeWon,
van Duijn Cornelia M.,
Heemst Diana,
Vandenput Liesbeth,
Vasan Ramachandran S.,
Völker Uwe,
Willems Sara M.,
Ohlsson Claes,
Wallaschofski Henri,
Kaplan Robert C.
Publication year - 2016
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12490
Subject(s) - igfbp3 , biology , single nucleotide polymorphism , expression quantitative trait loci , snp , genetics , genome wide association study , locus (genetics) , longevity , genotype , allele , gene , quantitative trait locus , genetic association , growth factor , receptor
Summary 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 ( IGF 1, IGFBP 3 , GCKR , TNS 3, GHSR , FOXO 3, ASXL 2, NUBP 2/ IGFALS , SORCS 2 , and CELSR 2 ). 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 SNP s at the loci IGFBP 3 and SORCS 2 . Analyses of SNP s, gene expression, and protein levels suggested that interplay between IGFBP 3 and genes within the NUBP 2 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 ASXL 2 , was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity‐associated variant rs2153960 ( FOXO 3) 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 CELSR 2 . 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 ( FOXO 3 ) and novel ( ASXL 2 ) longevity‐associated loci.