Association of the IGF1 gene with fasting insulin levels

Sara M. Willems, Belinda K. Cornes, Jennifer A. Brody, Alanna C. Morrison, Leonard Lipovich, Marco Dauriz, Yuning Chen, Ching Ti Liu, Denis V. Rybin, Richard A. Gibbs, Donna Muzny, James S. Pankow, Bruce M. Psaty, Eric Boerwinkle, Jerome I. Rotter, David S. Siscovick, Ramachandran S. Vasan, Robert C. Kaplan, Aaron Isaacs, Josée DupuisCornelia M. Van Duijn, James B. Meigs

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT =5.7 × 10-4). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional =0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.

Original languageEnglish (US)
Pages (from-to)1337-1343
Number of pages7
JournalEuropean Journal of Human Genetics
Volume24
Issue number9
DOIs
StatePublished - Aug 1 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Willems, S. M., Cornes, B. K., Brody, J. A., Morrison, A. C., Lipovich, L., Dauriz, M., Chen, Y., Liu, C. T., Rybin, D. V., Gibbs, R. A., Muzny, D., Pankow, J. S., Psaty, B. M., Boerwinkle, E., Rotter, J. I., Siscovick, D. S., Vasan, R. S., Kaplan, R. C., Isaacs, A., ... Meigs, J. B. (2016). Association of the IGF1 gene with fasting insulin levels. European Journal of Human Genetics, 24(9), 1337-1343. https://doi.org/10.1038/ejhg.2016.4