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.