Abstract
There is evidence across several species for genetic control of phenotypic variation of complex traits1,2,3,4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5,6,7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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Acknowledgements
We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506), the US National Institutes of Health (grants AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854 and GM057091) and the Australian Research Council (ARC grant DP1093502). A detailed list of acknowledgements by study is provided in the Supplementary Information. We apologize to authors whose work we could not cite owing to space restrictions.
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P.M.V., M.E.G. and J.Y. conceived and designed the study. J.Y. and P.M.V. derived the analytical theory. J.Y. performed the meta-analyses and simulations. J.Y. and P.M.V. wrote the first draft of the manuscript. J.Y., D.I.C., J.H.Z. and R.J.F.L. performed further statistical verification analyses. D.P.S., W.G.H., R.J.F.L., S.I.B. and H. Snieder contributed important additional concepts and critically reviewed the manuscript before submission. S.E.M., P.A.F.M., A.C.H., N.G.M., D.R.N. and G.W.M. contributed the individual-level genotype and phenotype data of the QIMR cohort. T.M.F., J.N.H. and R.J.F.L. liaised with the GIANT consortium for this project. The cohort-specific contributions of all other authors are provided in the Supplementary Information.
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Supplementary Information
This file contains Supplementary Figures 1-10, Supplementary Tables 1-5, Supplementary Notes and Data, Supplementary References, Supplementary Acknowledgements (study-specific) and Supplementary Author Contributions. Supplementary Tables 4, 5 and the Acknowledgements were corrected on 31 January 2013. (PDF 1652 kb)
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Yang, J., Loos, R., Powell, J. et al. FTO genotype is associated with phenotypic variability of body mass index. Nature 490, 267–272 (2012). https://doi.org/10.1038/nature11401
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DOI: https://doi.org/10.1038/nature11401
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