The genetics of human obesity

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Key Points

  • Obesity is a serious health issue in the developed world and is becoming increasingly important on a global scale. The development of an obesogenic environment, due to ease of access to highly calorific food and reduced energy expenditure in work and leisure activities, has increased the proportion of overweight individuals in society.

  • Over and above the increase in overweight individuals, there has been a dramatic rise in those who can be defined as morbidly obese. As suggested by the 'thrifty gene' hypothesis, these individuals might possess 'obesity-promoting' genetic variants that were previously advantageous, but that now lead them to become morbidly obese in the current environment.

  • The physiology of energy balance is complex, with the arcuate nucleus of the hypothalamus having a central role in this mechanism. Mouse models have been useful in initially highlighting many of the genes and proteins that are involved.

  • Rare, monogenic forms of human obesity — such as mutations in genes that encode leptin, its receptor, pro-opiomelanocortin, and the melanocortin 4 receptor — have provided insights into the pathogenesis of obesity. There are also syndromes where obesity is a component of the phenotype; however, their aetiology is more complex.

  • Heritability studies have demonstrated that genetics also has a significant role in common obesity, which is thought to be caused by a combination of multiple genetic and environmental factors.

  • Using both candidate-gene and whole-genome linkage strategies, novel genes and regions have been found to be linked and/or associated with obesity phenotypes. Studies to define the roles of these genes and their products in the pathophysiological mechanisms that lead to obesity are currently in progress.

  • New strategies, such as whole-genome association studies and the use of microarrays, could allow the identification of large numbers of genes that are involved in obesity in the near future.

Abstract

Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.

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Figure 1: Physiological regulation of energy balance.
Figure 2: Genetic-linkage map for obesity.

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Acknowledgements

The authors wish to acknowledge the continuing support for their research that is provided by the Medical Research Council and Imperial College London.

Author information

Correspondence to Philippe Froguel.

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The authors declare no competing financial interests.

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DATABASES

Entrez

AGRP

NPY

POMC

CART

PYY3–36

CCK

MC4R

SIM1

PPARG

OMIM

type II diabetes

Prader–Willi syndrome

Pseudohypoparathyroidism type 1A

Bardet–Biedl syndrome

Swiss-Prot

FURTHER INFORMATION

dbSNP — NCBI Single Nucleotide Polymorphism database

Genetic Association database

HUGO Gene Nomenclature Committee web site

International HapMap Project

Obesity Gene Map database

SNP Consortium

Glossary

BODY MASS INDEX

(BMI). An anthropometric measure of body mass that is calculated by dividing a person's weight in kilograms by the square of their height in metres.

HYPERPHAGIA

Ingestion of a greater than optimal quantity of food; an abnormally increased appetite for and consumption of food.

HYPOTONIA

Decreased muscle tone from the average and reduced resistance to passive stretching of muscles.

HYPOGONADOTROPIC HYPOGONADISM

Absent or decreased function of the male testis or the female ovary (the gonads). It results from the absence of the gonadal stimulating pituitary hormones, FSH (follicle stimulating hormone) and LH (luteinizing hormone).

UNIPARENTAL DISOMY

The presence in a cell of homologous chromosomes from the same parent, with no chromosome of that pair from the other parent. This can result from non-disjunction events during meiosis, and might be composed of both homologous chromosomes from one parent (heterodisomy) or a duplicate of one chromosome (isodisomy).

GS PROTEIN

The heterotrimeric guanine nucleotide-binding protein (G protein) that stimulates adenylyl cyclase and functions as a molecular switch in many signal-transduction pathways.

ROD-CONE DYSTROPHY

Hereditary, progressive degeneration of the neuroepithelium of the retina that is characterized by night blindness and progressive contraction of the visual field.

POLYDACTYLY

A developmental anomaly that is characterized by the presence of more than five fingers on the hand or more than five toes on the foot.

HERITABILITY

The proportion of phenotypic variance that is due to genetic effects.

SUBSCAPULAR SKINFOLD THICKNESS

The skinfold measure that is taken below the inferior angle of the scapula.

SUPRAILIAC SKINFOLD THICKNESS

The skinfold measure that is taken midway between the hip joint and the bottom of the ribcage.

METABOLIC EFFICIENCY

Energy intake per kilogram that is required to maintain bodyweight.

RELATIVE RISK

The ratio of the risk of the expression of a phenotype among individuals with a particular exposure, genotype or haplotype to the risk among those without that exposure, genotype or haplotype.

ADMIXTURE

The mixture of two or more genetically distinct populations.

HAPLOTYPE

A set of closely linked genetic markers on a single chromosome.

MINOR ALLELE FREQUENCY

The frequency of the less common allele of a polymorphism. It has a value between 0 and 0.5, and can vary between populations.

PROBAND

A subject that is ascertained on the basis of their phenotype; often used to identify affected families for genetic studies.

QUANTITATIVE TRAIT

A continuously varying trait; for example, weight, height and skin colour.

VARIANCE COMPONENTS METHOD

The variance components (VC) approach is a method that expresses the phenotypic variances and covariances among individuals as a function of the estimated number of shared alleles that are identical by descent at a given locus.

NUCLEAR FAMILY

A family that is composed of a father, mother and their children.

LONGITUDINAL PROSPECTIVE STUDIES

Studies in which individuals are followed up over time to assess who develops a certain outcome (often disease).

METABOLIC SYNDROME

The occurrence of hyperinsulinaemia, glucose intolerance, dyslipidaemia, hypertension and obesity in an individual.

STRATIFICATION

The presence of several subgroups within a study group, either through genuine population subdivision or recruitment bias. Differences in both allele frequency and disease prevalence between these subgroups can lead to spurious associations with disease.

MULTIPLE-HYPOTHESIS TESTING

Testing more than one hypothesis in an experiment. As a result, the probability of an unusual result occurring by chance in the entire experiment is higher than the individual significance value associated with that result.

PROSPECTIVE STUDY

A study in which participants are divided into groups that are exposed or not exposed to the intervention(s) of interest before the outcomes have occurred.

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Bell, C., Walley, A. & Froguel, P. The genetics of human obesity. Nat Rev Genet 6, 221–234 (2005) doi:10.1038/nrg1556

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