PT - JOURNAL ARTICLE AU - Andrew R Wood AU - Jessica Tyrell AU - Robin Beaumont AU - Samuel E. Jones AU - Marcus A. Tuke AU - Katherine S. Ruth AU - The GIANT consortium AU - Hanieh Yaghootkar AU - Rachel Freathy AU - Anna Murray AU - Timothy M. Frayling AU - Michael N. Weedon TI - Variants in the <em>FTO</em> and <em>CDKAL1</em> loci have recessive effects on risk of obesity and type 2 diabetes respectively AID - 10.1101/027490 DP - 2015 Jan 01 TA - bioRxiv PG - 027490 4099 - http://biorxiv.org/content/early/2015/09/24/027490.short 4100 - http://biorxiv.org/content/early/2015/09/24/027490.full 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.