Emerging data onFTO, the first obesity gene to be identified by genome-wide association studies, suggest a role for the encoded demethylase in nutrient sensing, regulation of mRNA translation and general growth. This Review discusses the genetic epidemiology of FTO and how its complex biology might link to the regulation of body weight. Single nucleotide polymorphisms (SNPs) that cluster in the first intron of fat mass and obesity associated (FTO) gene are associated obesity traits in genome-wide association studies. The minor allele increases BMI by 0.39 kg/m2 (or 1,130 g in body weight) and risk of obesity by 1.20-fold. This association has been confirmed across age groups and populations of diverse ancestry; the largest effect is seen in young adulthood. The effect of FTO SNPs on obesity traits in populations of African and Asian ancestry is similar or somewhat smaller than in European ancestry populations. However, the BMI-increasing allele in FTO is substantially less prevalent in populations with non-European ancestry. FTO SNPs do not influence physical activity levels; yet, in physically active individuals, FTO's effect on obesity susceptibility is attenuated by approximately 30%. Evidence from epidemiological and functional studies suggests that FTO confers an increased risk of obesity by subtly changing food intake and preference. Moreover, emerging data suggest a role for FTO in nutrient sensing, regulation of mRNA translation and general growth. In this Review, we discuss the genetic epidemiology of FTO and discuss how its complex biology might link to the regulation of body weight.

/pdf/the-bigger-picture-of-fto-the-first-gwas-identified-obesity-3q0ibczb9z.pdf

The bigger picture of FTO —the first GWAS-identified obesity gene

In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine.

Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N 6 -methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N 6 -methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N 6 -methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.

/pdf/a-link-between-fto-ghrelin-and-impaired-brain-food-cue-lcjfrvlg6f.pdf

A link between FTO, ghrelin, and impaired brain food-cue responsivity

Epidemiology and determinants of type 2 diabetes in south Asia

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)<P<5 × 10(-8), odds ratio (OR)  = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2 × 10(-23) < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.

https://handls.nih.gov/pubs/2014-Ng-PLoSgentics-10-e1004517.pdf

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.

/pdf/association-of-genetic-variation-in-fto-with-risk-of-obesity-4szt2xaqm6.pdf

Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians

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Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians