RT Journal Article
SR Electronic
T1 Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes respectively
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 027490
DO 10.1101/027490
A1 Andrew R Wood
A1 Jessica Tyrell
A1 Robin Beaumont
A1 Samuel E. Jones
A1 Marcus A. Tuke
A1 Katherine S. Ruth
A1 The GIANT consortium
A1 Hanieh Yaghootkar
A1 Rachel Freathy
A1 Anna Murray
A1 Timothy M. Frayling
A1 Michael N. Weedon
YR 2015
UL http://biorxiv.org/content/early/2015/09/25/027490.abstract
AB Genome-wide association studies have identified hundreds of common genetic variants associated with obesity and Type 2 diabetes. These studies have focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.To identify non-additive associations we performed a genome-wide association study using a dominance deviation model for BMI, obesity and Type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study.Known obesity-associated variants in FTO showed strong evidence for deviation from additivity (P=3×10−5) through a recessive effect of the BMI-increasing allele. The average BMI of individuals carrying 0, 1 or 2 BMI-raising alleles was 27.27kg/m2 (95% CI:27.22-27.31), 27.54kg/m2 (95% CI:27.50-27.58), and 28.07kg/m2 (95% CI:28.0-28.14), respectively. A similar effect was observed in 105,643 individuals from the GIANT consortium (P=0.003; Pmeta-analysis=1×10−7). We also detected a recessive effect (Pdomdev=5×10−4) at CDKAL1 for Type 2 diabetes risk. Homozygous risk allele carriers had an OR=1.48 (95% CI:1.32-1.65) in comparison to the heterozygous group that had an OR=1.06 (95% CI:0.99-1.14), a result consistent with a previous study. We did not identify any novel genome-wide associations.In conclusion, although we find no evidence for widespread non-additive effects contributing to the genetic risk of obesity and Type 2 diabetes, we find robust examples of recessive effects at the FTO and CDKAL1 loci.