Abstract
Aims/hypothesisGenome-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.MethodsWe 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.ResultsKnown obesity-associated variants in FTO showed strong evidence of deviation from additivity (pDOMDEV = 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 (pDOMDEV = 0.003; meta-analysis pDOMDEV = 1 × 10−7). For type 2 diabetes, we detected a recessive effect (pDOMDEV = 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/interpretationAlthough 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 materialsSummary 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3908-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Genome-wide association (GWA) studies have identified hundreds of variants associated with obesity and type 2 diabetes [1,2,3,4,5,6,7,8,9]
Conclusions/interpretation 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
Our analyses of 120,286 UK Biobank individuals suggest that most genetic variants associated with BMI and type 2 diabetes operate through a per-allele additive effect
Summary
Genome-wide association (GWA) studies have identified hundreds of variants associated with obesity and type 2 diabetes [1,2,3,4,5,6,7,8,9]. GWA studies of type 2 diabetes and obesity have usually focused on testing additive models. Non-additive effects include dominant and recessive effects. These effects are common in monogenic disorders, but there are only a few examples in common diseases and traits [10]. For obesity and type 2 diabetes, the strongest evidence of a non-additive effect is at the CDKAL1 locus, where a previous study demonstrated a recessive effect [11]. The GIANT Consortium previously tested 32 BMI-associated variants for deviations from the additive model but, overall, found no evidence of deviation from additivity in 105,643 individuals [5]
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