Association of the IGF1 gene with fasting insulin levels.

 
TitleAssociation of the IGF1 gene with fasting insulin levels.
Publication TypeJournal Article
Year of Publication2016
AuthorsWillems, SM, Cornes, BK, Brody, JA, Morrison, AC, Lipovich, L, Dauriz, M, Chen, Y, Liu, C-T, Rybin, DV, Gibbs, RA, Muzny, DM, Pankow, JS, Psaty, BM, Boerwinkle, E, Rotter, JI, Siscovick, DS, Vasan, RS, Kaplan, RC, Isaacs, A, Dupuis, J, van Duijn, CM, Meigs, JB
JournalEur J Hum Genet
Volume24
Issue9
Pagination1337-43
Date Published2016 Aug
ISSN1476-5438
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.

DOI10.1038/ejhg.2016.4
Alternate JournalEur. J. Hum. Genet.
PubMed ID26860063
PubMed Central IDPMC4989214
Grant ListR01 DK078616 / DK / NIDDK NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
HHSN268201100008 / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
HHSN268201100005 / HL / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
HHSN268201100011 / HL / NHLBI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HC-25195 / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100009 / HL / NHLBI NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
R01 AG031890 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States