Variants in the FTO and CDKAL1 loci have recessive effects on risk of obesity and type 2 diabetes respectively
Andrew R. Wood,
Samuel E Jones,
Marcus A. Tuke,
Katherine S. Ruth,
The GIANT consortium,
Timothy M. Frayling,
Posted 24 Sep 2015
bioRxiv DOI: 10.1101/027490 (published DOI: 10.1007/s00125-016-3908-5)
Posted 24 Sep 2015
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=3x10-5) 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/m2 (95% CI:27.22-27.31), 27.54kg/m2 (95% CI:27.50-27.58), and 28.07kg/m2 (95% CI:28.0-28.14), respectively. A similar effect was observed in 105,643 individuals from the GIANT consortium (P=0.003; Pmeta-analysis=1x10-7). We also detected a recessive effect (Pdomdev=5x10-4) 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.
- Downloaded 445 times
- Download rankings, all-time:
- Site-wide: 33,785 out of 84,583
- In genetics: 2,020 out of 4,440
- Year to date:
- Site-wide: 80,069 out of 84,583
- Since beginning of last month:
- Site-wide: 79,039 out of 84,583
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!