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.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site.Published (Open Access

Beaumont, R

Frayling, TM

Freathy, RM

GIANT consortium

Jones, SE

Murray, A

Ruth, KS

Tuke, MA

Tyrrell, J

Weedon, MN

Wood, AR

Yaghootkar, H

Diabetologia

PubMed

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

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. 

PuSH

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

Published onlineJOURNAL ARTICLEAIMS/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/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 × 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.ARW and TMF are supported by the European Research
Council (grant 323195: SZ-245 50371-GLUCOSEGENES-FP7-
IDEAS-ERC). RMF is a Sir Henry Dale Fellow (Wellcome Trust and
Royal Society; grant 104150/Z/14/Z). RB is funded by the Wellcome
Trust and Royal Society (grant 104150/Z/14/Z). JT is funded by the
European Regional Development Fund and a Diabetes Research and
Wellness Foundation fellowship. SEJ is funded by the Medical
Research Council (grant MR/M005070/1). MAT, MNW and AM are
supported by the Wellcome Trust Institutional Strategic Support Award
(WT097835MF). HY is funded by a European Research Council award
(323195). The funders had no influence on the study design, data collection
and analysis, decision to publish, or preparation of the manuscript

Open Research Exeter

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

Andrew R. Wood

null null

Jessica Tyrrell

Robin Beaumont

Samuel E. Jones

Marcus A. Tuke

Katherine S. Ruth

Hanieh Yaghootkar

Rachel M. Freathy

Anna Murray

Timothy M. Frayling

Michael N. Weedon

Springer - Publisher Connector

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

Crossref

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.Published (Open Access)This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text from the publisher's site

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

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