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Genetic Determinants of Childhood Obesity

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Abstract

Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes substantially to mortality in the United States by increasing the risk for type 2 diabetes, cardiovascular-related diseases, and other comorbidities. Despite environmental changes over past decades, including increases in high-calorie foods and sedentary lifestyles, there is very clear evidence of a genetic predisposition to obesity risk. Childhood obesity cases can be categorized in one of two ways: syndromic or non-syndromic. Syndromic obesity includes disorders such as Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. Non-syndromic cases of obesity can be further separated into rarer instances of monogenic obesity and much more common forms of polygenic obesity. The advent of genome-wide association studies (GWAS) and next-generation sequencing has driven significant advances in our understanding of the genetic contribution to childhood obesity. Many rare and common genetic variants have been shown to contribute to the heritability in obesity, although the molecular mechanisms underlying most of these variants remain unclear. An important caveat of GWAS efforts is that they do not strictly represent gene target discoveries, rather simply the uncovering of robust genetic signals. One clear example of this is with progress in understanding the key obesity signal harbored within an intronic region of the FTO gene. It has been shown that the non-coding region in which the variant actually resides in fact influences the expression of genes distal to FTO instead, specifically IRX3 and IRX5. Such discoveries suggest that associated non-coding variants can be embedded within or next to one gene, but commonly influence the expression of other, more distal effector genes. Advances in genetics and genomics are therefore contributing to a deeper understanding of childhood obesity, allowing for development of clinical tools and therapeutic agents.

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Authors and Affiliations

  1. Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, USA

    Sheridan H. Littleton & Struan F. A. Grant

  2. Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Robert I. Berkowitz

  3. Divisions of Genetics and Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, USA

    Struan F. A. Grant

  4. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA

    Struan F. A. Grant

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  1. Sheridan H. Littleton
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  2. Robert I. Berkowitz
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  3. Struan F. A. Grant
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Correspondence to Struan F. A. Grant.

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Funding

This work was supported by a grant from the National Institute of Child Health and Human Development (R01HD056465).

Conflicts of interest

The authors SHL and SFAG declare that they have no conflicts of interest. RIB has received funding from research grants provided to Children’s Hospital of Philadelphia from Eisai Inc. and NovoNordisk.

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SHL contributed the design of the manuscript. All authors drafted, revised, and approved the final manuscript.

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Littleton, S.H., Berkowitz, R.I. & Grant, S.F.A. Genetic Determinants of Childhood Obesity. Mol Diagn Ther 24, 653–663 (2020). https://doi.org/10.1007/s40291-020-00496-1

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