The genetics of adiposity

https://doi.org/10.1016/j.gde.2018.02.009Get rights and content

Genome-wide discovery efforts have identified more than 500 genetic loci associated with adiposity traits. The vast majority of these loci were found through large-scale meta-analyses for body mass index (BMI) and waist-to-hip ratio (WHR), and in European ancestry populations. However, alternative approaches, focusing on non-European ancestry populations, more refined adiposity measures, and low-frequency (minor allele frequency (MAF) < 5%) coding variants, identified additional novel loci that had not been identified before. Loci associated with overall obesity implicate pathways that act in the brain, whereas loci associated with fat distribution point to pathways involved in adipocyte biology. Pinpointing the causal gene within each locus remains challenging, but is a critical step towards translation of genome-wide association study (GWAS) loci into new biology. Ultimately, new genes may provide pharmacological targets for the development of weight loss drugs.

Introduction

Obesity is a major risk factor of disease, not only posing an enormous burden on people's personal health [1], but also on societies as a whole [2, 3]. Over the past four decades, the prevalence of obesity among adults has nearly quadrupled worldwide [4, 5]. While in most high-income countries the rise in BMI seems to have slowed down as of late, albeit at a high level, in many low-income and middle-income countries the increase continues. Particularly alarming is the global rise in obesity among children and adolescents [4, 5, 6].

Initiatives to prevent obesity or promote weight loss through lifestyle changes have limited success and are often short-lived, both at the community and individual levels [7, 8], suggesting that innate mechanisms, encoded by the genome, also contribute to energy homeostasis [9••]. Estimates of genetic contribution vary by study design and adiposity outcome, but are sufficiently high to warrant gene discovery studies (Table 1).

In the past 10 years, genome-wide association studies (GWASs) have been particularly effective in the identification of genetic loci associated with adiposity outcomes. However, translation of these loci into new biology has been challenging. Here, I review recent progress and insights gained from these discoveries.

Section snippets

Conventional GWAS  Common (MAF  5%) variants for commonly studied adiposity phenotypes

In 2007, GWASs discovered the first genetic locus in FTO that showed robust association with BMI and obesity risk [10, 11]. More than 500 genetic loci, for a range of adiposity traits, have since been identified (Figure 1). The vast majority of these (92%) were first identified for body mass index (BMI; n = 341 loci), a proxy for overall adiposity, and for BMI-adjusted waist-to-hip ratio (WHRadjBMI; N = 129), a proxy for body fat distribution. Because data on BMI and WHR are easily obtained, sample

Alternative approaches for gene discovery

Conventional GWAS, described above, have been very fruitful, not only because of the large sample, but also because the studied variants are common (MAF > 5%); both are contributors to increased statistical power for discovery. However, several other approaches have identified new loci through leveraging specific phenotypic and genotypic features.

Genetic correlation and Mendelian randomization

Genetic correlation and Mendelian randomization are complementary approaches to assess shared etiology and causal relationships between adiposity and other traits.

Genetic correlation studies correlate SNP-association effects of one trait with those of another trait. SNP-association effects of BMI and WHRadjBMI were found to positively correlate with those of cardiometabolic traits, excessive daytime sleepiness, sleep duration [60, 61, 62], and negatively with those for anorexia nervosa, age at

Genetic information to predict obesity

Historically, genetic tests have been used to provide a genetic diagnosis to patients with rare forms of extreme and early-onset obesity that may be due to a single mutation [84]. For some patients, such a genetic diagnosis has been instrumental in their treatment [85, 86]. As more variants are being discovered and genome sequencing is becoming mainstream, there is a growing expectation that genetic tests will help clinicians predict and diagnose patients’ risks of complex disease, such as

Conclusions and future perspectives

In the past decade, large-scale genome-wide discovery efforts have uncovered numerous new loci that harbor genetic variants associated with adiposity traits. With the advent of additional large population studies (e.g. UK Biobank, Million Veterans Project, All of Us), the number of loci will continue to increase rapidly in coming years. Preliminary analyses suggest that these loci highlight pathways that broadly overlap with the biology previously identified in extreme models of obesity in

Conflict of interest statement

Nothing declared.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Ruth Loos is supported by the National Institutes of Health [R01 DK107786, R01 DK110113, U01HG007417].

References (97)

  • K. Silventoinen et al.

    Differences in genetic and environmental variation in adult body mass index by sex, age, time period, and region: an individual-based pooled analysis of 40 twin cohorts

    Am J Clin Nutr

    (2017)
  • M.R. Robinson et al.

    Genotype-covariate interaction effects and the heritability of adult body mass index

    Nat Genet

    (2017)
  • Collaborators GBDO et al.

    Health effects of overweight and obesity in 195 countries over 25 years

    N Engl J Med

    (2017)
  • NCD Risk Factor Collaboration

    Trends in adult body-mass index in 200 countries from 1975 to 2014: A pooled analysis of 1698 population-based measurement studies with 19.2 million participants

    Lancet

    (2016)
  • Fact Sheet: Obesity and Overweight

    (2017)
  • NCD Risk Factor Collaboration et al.

    Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults

    Lancet

    (2017)
  • M. Ezzati et al.

    Can noncommunicable diseases be prevented? Lessons from studies of populations and individuals

    Science

    (2012)
  • S. Ghosh et al.

    Convergence between biological, behavioural and genetic determinants of obesity

    Nat Rev Genet

    (2017)
  • T.M. Frayling et al.

    A common variant in the fto gene is associated with body mass index and predisposes to childhood and adult obesity

    Science

    (2007)
  • A. Scuteri et al.

    Genome-wide association scan shows genetic variants in the fto gene are associated with obesity-related traits

    PLoS Genet

    (2007)
  • A.E. Locke et al.

    Genetic studies of body mass index yield new insights for obesity biology

    Nature

    (2015)
  • D. Shungin et al.

    New genetic loci link adipose and insulin biology to body fat distribution

    Nature

    (2015)
  • http://www.broadinstitute.org/collaboration/giant/index.Php/main_page....
  • M. Akiyama et al.

    Genome-wide association study identifies 112 new loci for body mass index in the japanese population

    Nat Genet

    (2017)
  • M.C.Y. Ng et al.

    Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of african ancestry: African ancestry anthropometry genetics consortium

    PLoS Genet

    (2017)
  • H.K. Finucane et al.

    Partitioning heritability by functional annotation using genome-wide association summary statistics

    Nat Genet

    (2015)
  • Y.C. Tung et al.

    Obesity and fto: changing focus at a complex locus

    Cell Metab

    (2014)
  • M. Claussnitzer et al.

    Fto obesity variant circuitry and adipocyte browning in humans

    N Engl J Med

    (2015)
  • G. Stratigopoulos et al.

    Hypomorphism for rpgrip1l, a ciliary gene vicinal to the fto locus, causes increased adiposity in mice

    Cell Metab

    (2014)
  • G. Stratigopoulos et al.

    Hypomorphism of fto and rpgrip1l causes obesity in mice

    J Clin Invest

    (2016)
  • L. Wiemerslage et al.

    The drosophila ortholog of tmem18 regulates insulin and glucagon-like signaling

    J Endocrinol

    (2016)
  • T. Rathjen et al.

    Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1

    Nat Neurosci

    (2017)
  • X. Yan et al.

    Cadm2 regulates body weight and energy homeostasis in mice

    Mol Metab

    (2017)
  • R.A. Watson et al.

    Lyplal1 is dispensable for normal fat deposition in mice

    Dis Models Mech

    (2017)
  • J.E. Siljee et al.

    Subcellular localization of mc4r with adcy3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity

    Nat Genet

    (2018)
  • Y. Lu et al.

    New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

    Nat Commun

    (2016)
  • T.O. Kilpelainen et al.

    Genetic variation near irs1 associates with reduced adiposity and an impaired metabolic profile

    Nat Genet

    (2011)
  • E. Araki et al.

    Alternative pathway of insulin signalling in mice with targeted disruption of the irs-1 gene

    Nature

    (1994)
  • H. Tamemoto et al.

    Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1

    Nature

    (1994)
  • H. Miki et al.

    Essential role of insulin receptor substrate 1 (irs-1) and irs-2 in adipocyte differentiation

    Mol Cell Biol

    (2001)
  • Y.H. Tseng et al.

    Differential roles of insulin receptor substrates in brown adipocyte differentiation

    Mol Cell Biol

    (2004)
  • M.C. Zillikens et al.

    Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

    Nat Commun

    (2017)
  • A.Y. Chu et al.

    Multiethnic genome-wide meta-analysis of ectopic fat depots identifies loci associated with adipocyte development and differentiation

    Nat Genet

    (2017)
  • T.O. Kilpelainen et al.

    Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    Nat Commun

    (2016)
  • Y.H. Hong et al.

    Up-regulation of adipogenin, an adipocyte plasma transmembrane protein, during adipogenesis

    Mol Cell Biochem

    (2005)
  • J.Y. Kim et al.

    Cloning, expression, and differentiation-dependent regulation of smaf1 in adipogenesis

    Biochem Biophys Res Commun

    (2005)
  • I. Tachmazidou et al.

    Whole-genome sequencing coupled to imputation discovers genetic signals for anthropometric traits

    Am J Hum Genet

    (2017)
  • A.E. Hendricks et al.

    Rare variant analysis of human and rodent obesity genes in individuals with severe childhood obesity

    Sci Rep

    (2017)
  • Cited by (89)

    • Obesity Management in Children and Adolescents

      2023, Gastroenterology Clinics of North America
    • Obesity in the Tropics

      2023, Manson's Tropical Diseases, Fourth Edition
    View all citing articles on Scopus
    View full text