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Genetics of Obesity: What have we Learned?

ABSTRACT: Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.

SUBMITTER: Choquet H

PROVIDER: S-EPMC3137002 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Genetics of Obesity: What have we Learned?

Choquet Hélène H Meyre David D

Current genomics 20110501 3

Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics ...[more]

PMID: 22043165

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Project description:Purpose of reviewThe prevalence of obesity continues to rise, fueling a global public health crisis characterized by dramatic increases in type 2 diabetes, cardiovascular disease, and many cancers. In the USA, several minority populations, who bear much of the obesity burden (47% in African Americans and Hispanic/Latinos, compared to 38% in European descent groups), are particularly at risk of downstream chronic disease. Compounding these disparities, most genome-wide association studies (GWAS)-including those of obesity-have largely been conducted in populations of European or East Asian ancestry. In fact, analysis of the GWAS Catalog found that while the proportion of participants of non-European or non-Asian descent had risen from 4% in 2009 to 19% in 2016, African-ancestry participants are still just 3% of GWAS, Hispanic/Latinos are < 0.5%, and other ancestries are < 0.3% or not represented at all. This review summarizes recent developments in obesity genomics in US minority populations, with the goal of reducing obesity health disparities and improving public health programs and access to precision medicine.Recent findingsGWAS of populations with the highest burden of obesity are essential to narrow candidate variants for functional follow-up, to identify additional ancestry-specific variants that contribute to individual genetic susceptibility, and to advance both public health and precision medicine approaches to obesity. Given the global public health burden posed by obesity and downstream chronic conditions which disproportionately affect non-European populations, GWAS of obesity-related traits in diverse populations is essential to (1) locate causal variants in GWAS-identified regions through fine mapping, (2) identify variants which influence obesity across ancestries through generalization, and (3) discover novel ancestry-specific variants which may be low frequency in European populations but common in other groups. Recent efforts to expand obesity genomic studies to understudied and underserved populations, including AAAGC, PAGE, and HISLA, are working to reduce obesity health disparities, improve public health, and bring the promise of precision medicine to all.

Project description:Recent advances in human genetics have revealed a number of genes influencing the susceptibility to obesity and related conditions, but it is likely that their contribution to disease is contingent on numerous environmental factors. As the obesity epidemic has occurred over a relatively short period of recent history, use of gene-by-year of birth analysis may be a useful approach for quantifying, in aggregate, the interaction between genetic susceptibility to obesity and the numerous known and unknown environmental factors that have changed during nutrition and health transitions globally during this recent increase in obesity rates. Evidence from one family-based longitudinal study set in the United States is showcased, which points to significant increases in the effect of common genetic variants on childhood and adulthood BMI over an 80 year period spanning from 1929 to the present. First, common genetic variants previously known to be associated with age at menarche through genome-wide association analysis were examined in aggregate using a genetic risk score approach. The menarche genetic risk score, composed of 42 single-nucleotide polymorphisms (SNPs) was significantly associated with peri-pubertal BMI in both boys and girls, but the magnitude of the association was strongly dependent on year of birth, with greater effect as birth year increased. Second, a similar approach was taken using instead a BMI genetic risk score composed of 32 common variants previously found to be associated with BMI. This score was strongly associated with adulthood BMI, waist circumference, and skinfold thickness, as expected, but the magnitude of the association increased with later year of birth. Such gene-environment interactions call for greater focus on the mechanisms by which environmental factors impact the functional output of the human genome, including how epigenetic mechanisms may be altered during social, technological, nutritional, and ecological transitions.

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Genetics of Obesity: What have we Learned?

Publications

Genetics of Obesity: What have we Learned?

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