Published in:
Open Access 01-06-2016 | Article
Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively
Published in: Diabetologia | Issue 6/2016
Login to get accessAbstract
Aims/hypothesis
Genome-wide association (GWA) studies have identified hundreds of common genetic variants associated with obesity and type 2 diabetes. These studies have usually focused on additive association tests. Identifying deviations from additivity may provide new biological insights and explain some of the missing heritability for these diseases.
Methods
We performed a GWA study using a dominance deviation model for BMI, obesity (29,925 cases) and type 2 diabetes (4,040 cases) in 120,286 individuals of British ancestry from the UK Biobank study. We also investigated whether single nucleotide polymorphisms previously shown to be associated with these traits showed any enrichment for departures from additivity.
Results
Known obesity-associated variants in FTO showed strong evidence of deviation from additivity (p
DOMDEV = 3 × 10−5) through a recessive effect of the allele associated with higher BMI. The average BMI of individuals carrying zero, one or two BMI-raising alleles was 27.27 (95% CI 27.22, 27.31) kg/m2, 27.54 (95% CI 27.50, 27.58) kg/m2 and 28.07 (95% CI 28.00, 28.14) kg/m2, respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p
DOMDEV = 0.003; meta-analysis p
DOMDEV = 1 × 10−7). For type 2 diabetes, we detected a recessive effect (p
DOMDEV = 5 × 10−4) at CDKAL1. Relative to homozygous non-risk allele carriers, homozygous risk allele carriers had an OR of 1.48 (95% CI 1.32, 1.65), while the heterozygous group had an OR of 1.06 (95% CI 0.99, 1.14), a result consistent with that of a previous study. We did not identify any novel associations at genome-wide significance.
Conclusions/interpretation
Although we found no evidence of widespread non-additive genetic effects contributing to obesity and type 2 diabetes risk, we did find robust examples of recessive effects at the FTO and CDKAL1 loci.
Access to research materials
Summary statistics are available at www.t2diabetesgenes.org and by request (a.r.wood@exeter.ac.uk). All underlying data are available on application from the UK Biobank.