University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
Nature. 2012 Oct 11;490(7419):267-72. doi: 10.1038/nature11401. Epub 2012 Sep 16.
There is evidence across several species for genetic control of phenotypic variation of complex traits, 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), 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 BMI, possibly mediated by DNA methylation. 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.
有证据表明，多个物种的复杂性状表型变异受遗传控制，即表型之间的差异取决于基因型。了解变异性的遗传控制在进化生物学、农业选择计划和人类医学中都很重要，但对于复杂性状，尚未确定与变异（与平均值相反）相关的单个遗传变异。在这里，我们使用人类群体中约 170,000 个样本对身高和体重指数（BMI）的表型变异进行了全基因组关联研究的荟萃分析。我们报告了证据表明，FTO 基因座上的单核苷酸多态性（SNP）rs7202116 与肥胖（通过每个 rs7202116 基因型的平均 BMI 来衡量）有关，也与表型变异性有关。我们表明，结果不是由于尺度效应或其他伪影引起的，并且在 FTO 以外的 BMI 或任何高度的其他基因座上，都没有发现其他实验性显著证据表明对变异性有影响。FTO 基因座上相反纯合基因型个体的 BMI 变异差异约为 7%，相当于体重标准差差异约为 0.5 公斤。我们的结果表明，可以发现与变异性相关的遗传变异，并且 FTO 基因座的基因型可以部分解释肥胖的个体间变异性。这些结果与报告的 BMI 的 FTO 与环境相互作用一致，可能由 DNA 甲基化介导。我们对其他 SNPs 的 BMI 结果和我们对所有 SNPs 的身高结果表明，大多数遗传变异，包括那些影响平均身高或平均 BMI 的遗传变异，与表型方差无关，或者它们对变异性的影响太小，即使样本量大于 100,000，也无法检测到。
