Variants in theFTOandCDKAL1loci have recessive effects on risk of obesity and type 2 diabetes respectively

ABSTRACT 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/m 2 (95% CI:27.22-27.31), 27.54kg/m 2 (95% CI:27.50-27.58), and 28.07kg/m 2 (95% CI:28.0-28.14), respectively. A similar effect was observed in 105,643 individuals from the GIANT consortium ( P =0.003; P meta-analysis =1×10 −7 ). We also detected a recessive effect ( P domdev =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.