title: Association of the IGF1 gene with fasting insulin levels.
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.
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Sara M
authors: SM
authors: Willems
authors: Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors: Belinda K
authors: BK
authors: Cornes
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Jennifer A
authors: JA
authors: Brody
authors: School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Alanna C
authors: AC
authors: Morrison
authors: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.|Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.
authors: Leonard
authors: L
authors: Lipovich
authors: Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.|Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona Medical School and Hospital Trust of Verona, Verona, Italy.
authors: Marco
authors: M
authors: Dauriz
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: Yuning
authors: Y
authors: Chen
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors: Ching-Ti
authors: CT
authors: Liu
authors: Boston University Data Coordinating Center, Boston, MA, USA.
authors: Denis V
authors: DV
authors: Rybin
authors: Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors: Richard A
authors: RA
authors: Gibbs
authors: Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors: Donna
authors: D
authors: Muzny
authors: Division of Epidemiology and Community Health (J.S.P.), University of Minnesota, Minnesota, MN, USA.
authors: James S
authors: JS
authors: Pankow
authors: Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors: Bruce M
authors: BM
authors: Psaty
authors: School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA.|Human Genome Sequencing Center, Baylor College of Medicine, University of Texas Health Science Center, Houston, TX, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: New York Academy of Medicine, New York, NY, USA.
authors: David S
authors: DS
authors: Siscovick
authors: Cardiology Section, Department of Preventive Medicine and Epidemiology, Boston University School of Medicine, Boston, MA, USA.|National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors: Ramachandran S
authors: RS
authors: Vasan
authors: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
authors: Robert C
authors: RC
authors: Kaplan
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Aaron
authors: A
authors: Isaacs
authors: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.|National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
authors: Josée
authors: J
authors: Dupuis
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: Cornelia M
authors: CM
authors: van Duijn
authors: Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors: James B
authors: JB
authors: Meigs
mesh_terms: D000328:Adult; D000368:Aged; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: C583557:IGF1 protein, human; D007328:Insulin; D007334:Insulin-Like Growth Factor I