The genetic contribution to non-syndromic human obesity

• Published in: Nature reviews. Genetics Vol. 10; no. 7; pp. 431 - 442
• Main Authors: Walley, Andrew J., Asher, Julian E., Froguel, Philippe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2009; Nature Publishing Group
• Subjects: Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Body fat; Body mass index; Cancer Research; Energy; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Function; Gene mutations; Genes; Genetic aspects; Genetic Markers; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human; Genomes; Health aspects; Human Genetics; Humans; Hypotheses; Medical sciences; Metabolic diseases; Obesity; Obesity - genetics; Oxidation; Physiology; Polymorphism, Single Nucleotide; review-article; Risk factors; Thermogenesis; France; United States > US; Human; Obesity; Genetics; Review; Nutritional status; Nutrition disorder
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg2594

Key Points Obesity is an important disease globally, and has resulted in significant increases in morbidity and mortality in both the developed and developing worlds. There are many proposed explanations for the current obesity epidemic, but it is clear that genetics plays a significant part in whether a person becomes obese by affecting susceptibility to the current obesogenic environment, which is characterized by easy access to high-calorie food and reduced energy expenditure owing to decreased levels of physical activity in daily life. Although the precise physiological basis of obesity remains unclear, skewed energy balance, abnormalities of fat storage and mobilization, and disordered feeding behaviour may all play a part. Both genome-wide linkage scans and candidate gene association studies have had limited success in identifying genes underlying non-syndromic obesity, although genes responsible for monogenic obesity have been identified. Recently, the genome-wide association scan method has been used to successfully identify many novel SNPs associated with non-syndromic obesity. These results have significantly increased the number of obesity-related loci for which there is strong statistical evidence at the genome-wide level. The question remains why analysis of SNPs has not identified any variants of sufficiently large genetic effect to account for the level of heritability observed in obesity. Other forms of genomic variation may account for this, for example, low frequency SNPs, copy number variants and epigenetic modifications. Key strategies for the future of genetic studies in obesity include improving subject selection, phenotype measurement, and genome-wide study design. A systems-based approach to synthesizing genome-wide data sets is likely to be a fruitful approach to identifying obesity genes. Recent genome-wide studies have identified many common variants that are associated with non-syndromic obesity, providing new opportunities to explore its biological basis. Understanding the roles of epigenetics and of rare and copy number variants are important goals for the future. The last few years have seen major advances in common non-syndromic obesity research, much of it the result of genetic studies. This Review outlines the competing hypotheses about the mechanisms underlying the genetic and physiological basis of obesity, and then examines the recent explosion of genetic association studies that have yielded insights into obesity, both at the candidate gene level and the genome-wide level. With obesity genetics now entering the post-genome-wide association scan era, the obvious question is how to improve the results obtained so far using single nucleotide polymorphism markers and how to move successfully into the other areas of genomic variation that may be associated with common obesity.