Article

FTO genotype is associated with phenotypic variability of body mass index

University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
Nature (Impact Factor: 42.35). 09/2012; 490(7419):267-72. DOI: 10.1038/nature11401
Source: PubMed

ABSTRACT 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.

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    • "consistently the most prevalent genetic variant for human BMI (Speliotes et al. 2010, Yang et al. 2012) and, the latest GWAS meta-analysis on 249 796 adults, established an unambiguous effect size of 0.39 kg m À2 per FTO effect allele (P-value<10 À120 ) (Speliotes et al. 2010). The association between polymorphisms in the FTO gene and adult BMI is robust in both genders with consistent effect in almost all ethnic groups studied although differences exist in haplotype blocks and frequency of polymorphisms between populations [see (Jacobsson et al. 2013) for review]. "
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    • "GWAS has had many successes. Many common polymorphisms have now been found that increase genetic risk for AD (Harold et al. 2009; Lambert et al. 2009; Naj et al. 2011), age-related cognitive decline (Davies et al. 2012), schizophrenia (Almasy et al. 2008; Stefansson et al. 2009; Ripke et al. 2011; Rietschel et al. 2012), bipolar disorder (Sklar et al. 2011; Cichon et al. 2011) as well as obesity (Yang et al. 2012), alcohol drinking (Schumann et al. 2011), tobacco smoking (Thorgeirsson et al. 2008), cardiovascular disease (CARDIoGRAMplusC4D Consortium et al. 2013), osteoporosis (Estrada et al. 2012), prevalent psychiatric disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium et al. 2013) and for many other traits and diseases. "
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    • "consistently the most prevalent genetic variant for human BMI (Speliotes et al. 2010, Yang et al. 2012) and, the latest GWAS meta-analysis on 249 796 adults, established an unambiguous effect size of 0.39 kg m À2 per FTO effect allele (P-value<10 À120 ) (Speliotes et al. 2010). The association between polymorphisms in the FTO gene and adult BMI is robust in both genders with consistent effect in almost all ethnic groups studied although differences exist in haplotype blocks and frequency of polymorphisms between populations [see (Jacobsson et al. 2013) for review]. "
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    ABSTRACT: It is becoming increasingly recognised that early-life nutritional, metabolic and environmental factors can have a long term impact on the early onset of obesity, type 2 diabetes and cardiovascular diseases. Numerous experimental and epidemiological observations support the concept that an individual's response to its adult life-style and nutritional environment depends not only on their genetic susceptibility but also their previous early-life experiences. The current research challenge is to determine the primary pathways contributing to "non- or epi-genetic" causes of excess adult weight gain and adiposity. Evidence from the fields of genetic epidemiology, life-course modelling and diet-induced fetal programming all support a role for the FTO gene in this complex biological interaction. It may provide a missing link in the developmental regulation of energy metabolism. Our review therefore considers the role of the FTO gene in the early-life determination of body weight, body composition and energy balance. We will summarise current knowledge on FTO biology combining human genetic epidemiology, molecular models and findings from animal studies. Notably, we will focus on the role of FTO in energy balance in humans, the importance of FTO polymorphisms in childhood growth and the impact of fetal nutrition. Ultimately we propose a new hypothesis for future research designed to understand the role of FTO in setting gene expression in metabolically active tissues. This article is protected by copyright. All rights reserved.
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