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

• Published in: Aging cell Vol. 15; no. 5; pp. 811 - 824
• Main Authors: 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, Ming‐Huei, Chen, Tai C., Chen, Yii‐Der 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, Houwing‐Duistermaat, Jeanine J., Hu, Frank, Hunter, David J., Husemoen, Lise L., Isaacs, Aaron, Jacobs, Kevin B., Janssen, Joop A. M. J. L., Jansson, John‐Olov, 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, Hae‐Won, van Duijn, Cornelia M., Heemst, Diana, Vandenput, Liesbeth, Vasan, Ramachandran S., Völker, Uwe, Willems, Sara M., Ohlsson, Claes, Wallaschofski, Henri, Kaplan, Robert C.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2016; Wiley Open Access; John Wiley and Sons Inc
• Subjects: Adult; Aging; Aging - blood; Aging - genetics; Analysis; Applications; Basic Medicine; Bioinformatics; Cancer; Computer Science; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Gene expression; Gene Expression Regulation; Genetic research; Genetics; Genome-Wide Association Study; Genomes; genomewide association study; growth hormone axis; Human genetics; Humans; IGF-I; IGFBP-3; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 3 - blood; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor I; Insulin-Like Growth Factor I - genetics; Life Sciences; longevity; Male; Medical and Health Sciences; Medical Biotechnology; Medical Genetics; Medical Genetics and Genomics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk bioteknologi; Medicinsk genetik; Medicinsk genetik och genomik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Metabolome; Metabolome - genetics; Methodology; Oncology, Experimental; Original; Protein binding; Proteins; Quantitative Trait Loci; Quantitative Trait Loci - genetics; Quantitative Trait, Heritable; Regulatory Sequences, Nucleic Acid; Regulatory Sequences, Nucleic Acid - genetics; Santé publique et épidémiologie; Single nucleotide polymorphisms; Statistics; Type 2 diabetes; genomewide association study; growth hormone axis; longevity; IGF-I; aging; IGFBP-3
• ISSN: 1474-9718; 1474-9726; 1474-9726; 1474-9728
• DOI: 10.1111/acel.12490

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 (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.