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Wood, A.R.* ; Tyrrell, J.* ; Beaumont, R.* ; Jones, S.E.* ; Tuke, M.A.* ; Ruth, K.S.* ; Yaghootkar, H.* ; Freathy, R.M.* ; Murray, A.* ; Frayling, T.M.* ; Weedon, M.N.* ; GIANT Consortium (Chen, C.M. ; Gieger, C. ; Grallert, H. ; Heid, I.M. ; Heinrich, J. ; Illig, T. ; Lamina, C. ; Meitinger, T. ; Peters, A. ; Rzehak, P. ; Thiering, E. ; Wichmann, H.-E.)

Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes, respectively.

Diabetologia 59, 1214-1221 (2016)
Publ. Version/Full Text Research data DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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 x 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/m(2), 27.54 (95% CI 27.50, 27.58) kg/m(2) and 28.07 (95% CI 28.00, 28.14) kg/m(2), respectively. A similar effect was observed in 105,643 individuals from the GIANT Consortium (p(DOMDEV) = 0.003; meta-analysis p(DOMDEV) = 1 x 10(-7)). For type 2 diabetes, we detected a recessive effect (p(DOMDEV) = 5 x 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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Association Analysis ; Bmi ; Cdkal1 ; Fto ; Genetics ; Non-additive Effects ; Type 2 Diabetes ; Uk Biobank; Body-mass Index; Scale Association Analysis; Genome-wide Association; Genetic Architecture; Susceptibility Loci; Complex Traits; Metaanalysis; Insights
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 59, Issue: 6, Pages: 1214-1221 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)