Aris IM, Bernard JY, Chen L‐W, et al. Modifiable risk factors in the first 1000 days for subsequent risk of childhood overweight in an Asian cohort: significance of parental overweight status. Int J Obes 2018; 42(1):44–51. doi:10.1038/ijo.2017.178
124 124. Dabelea D, Mayer‐Davis EJ, Lamichhane AP, et al. Association of intrauterine exposure to maternal diabetes and obesity with type 2 diabetes in youth: the SEARCH Case‐Control Study. Diabetes Care 2008; 31(7):1422–6. doi:10.2337/dc07‐2417
125 125. Ogden CL, Carroll MD, Fakhouri TH, et al. Prevalence of obesity among youths by household income and education level of head of household ‐ United States 2011–2014. MMWR Morb Mortal Wkly Rep 2018; 67(6):186–9. doi:10.15585/mmwr.mm6706a3
126 126. Weden MM, Brownell P, Rendall MS. Prenatal, perinatal, early life, and sociodemographic factors underlying racial differences in the likelihood of high body mass index in early childhood. Am J Public Health 2012; 102(11):2057–67. doi:10.2105/AJPH.2012.300686
127 127. Taveras EM, Gillman MW, Kleinman KP, Rich‐Edwards JW, Rifas‐Shiman SL. Reducing racial/ethnic disparities in childhood obesity: the role of early life risk factors. JAMA Pediatr 2013; 167(8):731–8. doi:10.1001/jamapediatrics.2013.85
128 128. Pan L, Freedman DS, Park S, Galuska DA, Potter A, Blanck HM. Changes in obesity among US children aged 2 through 4 years enrolled in WIC during 2010–2016. JAMA 2019; 321(23):2364–6. doi:10.1001/jama.2019.5051
129 129. Daepp MIG, Gortmaker SL, Wang YC, Long MW, Kenney EL. WIC food package changes: trends in childhood obesity prevalence. Pediatrics 2019; 143(5):e20182841. doi:10.1542/peds.2018‐2841
4 Genes and Obesity
I. Sadaf Farooqi
Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK
Introduction
Obesity arises from the interaction between genetic, environmental, and behavioral factors acting through the physiologic mediators of energy intake and energy expenditure. Body weight is the archetypal polygenic trait, a quantitative phenotype that usually fails to display a Mendelian pattern of inheritance because it is influenced by many different regions of the genome [1]. The concept that environmental factors operate on an underlying pool of genes that contribute to obesity susceptibility has important implications for our approach to the prevention and treatment of obesity. If some environmental variables manifest themselves only on certain genotypes, efforts to prevent obesity at a public health level can be focused on recognition and counseling of susceptible individuals. In addition, appreciating the importance of genetic variation as an underlying cause helps to dispel the notion that obesity represents an individual fault in behavior and provides a starting point for efforts to identify the genes involved.
In the last 20 years, several single‐gene defects causing severe human obesity have been identified. Studies of patients with mutations in these molecules have shed light on the physiologic role of such molecules in the regulation of body weight in humans and provided new treatment for subgroups of people with severe obesity.
Historical perspective
Obesity, defined as an excess of body fat to a level that adversely affects health, is frequently considered to be a “modern” disease – a reflection of the excesses of Western urbanized society. However, artifacts dating from the Palaeolithic Stone Age clearly represent subjects with an excess of body fat, and descriptions of individuals with obesity have emerged in manuscripts and medical texts from many of the ancient civilizations, from Mesopotamia to Arabia, China to India. This historical evidence suggests that independent of diet and geographical region, throughout history, some individuals have harbored the propensity to store excess energy as fat.
Gene–environment interactions
The increase in the prevalence of obesity in the last 30 years demonstrates the importance of changing environmental factors, in particular the increased availability of cheap, palatable, energy‐dense foods and the reduction in physical activity during work and leisure time. Further evidence for the critical role of environmental factors in the development of obesity comes from migrant studies and the “westernization” of diet and lifestyles in developing countries. A marked change in body mass index (BMI) is frequently witnessed in migrant studies, where people with a common genetic heritage live under new environmental circumstances. Pima Indians, for example, living in the United States are on average 25 kg heavier than Pima Indians living in Mexico [2]. A similar trend is seen for Africans living in the United States and Asians living in the United Kingdom. Moreover, within some ethnic groups the prevalence of obesity has increased very dramatically not only amongst migrants but also amongst the indigenous population. In fact, the prevalence of obesity is currently more than 60% in Nauruan men and women in Micronesia and amongst Polynesians in Western Samoa, suggesting that people from these ethnic groups are more susceptible to developing obesity and that environmental factors have varying effects depending upon genetic background.
Evidence for the heritability of fat mass
There is considerable evidence to suggest that, like height, weight is a heritable trait. Genetic epidemiologic studies in different populations can attribute the underlying phenotypic variance of a trait to genetic and/or environmental sources. Longitudinal data from one of the largest family studies, the Quebec Family Study of over 400 families, suggest a significant cross‐trait familial resemblance for parent–offspring (0.20–0.25) and sibling relationships (0.25–0.35) [3]. However, in traditional nuclear families, family members generally share both genes and environment to some degree, so it is difficult to assess the contribution of each component.
Adoption studies
Complete adoption studies are useful in separating the common environmental effects since adoptive parents and their adoptive offspring share only environmental sources of variance, whilst the adoptees and their biologic parents share only genetic sources of variance. One of the largest series, based on over 5000 subjects from the Danish adoption register, which contains complete and detailed information on the biologic parents, showed a strong relationship between the BMI of adoptees and biologic parents across the whole range of body fatness but none when compared with the adoptive parents [1]. The Danish group has also shown a close correlation between BMI of adoptees and their biologic full siblings who were reared separately by the biologic parents of the adoptees, and a similar but weaker relationship with half‐siblings [4].
Twin studies
Traditionally the most favored model for separation of the genetic component of variance is based on studies of twins, as monozygotic co‐twins share 100% of their genes and dizygotes 50% on average. Heritability estimates the proportion of the total variance attributable to genetic variation under a polygenic model by comparing the similarity of a trait within monozygotic twins with the similarity within dizygotic twins. Heritability is a function of both the number of genes influencing a phenotype and the proportion of phenotypic variation accounted for by each of these genes. The advantage of studies of the heritability of BMI is that age‐dependent influences of genes or environmental factors are the same for both twins. Genetic contribution to the BMI has been estimated to be 64–84% [5].
The study of monozygotic twins reared apart has all the advantages of a twin study but does not rely on the equal environmental exposure assumption. Correlation of monozygotic twins reared apart is virtually a direct estimate of the heritability, although monozygotic twins do share the intrauterine environment, which may contribute to lasting differences in body mass in later life. Estimates vary from 40 to 70%, depending on the age at the separation of twins and the length of follow‐up. Longitudinal data from Virginia looking at adult twins and their offspring have reported a heritability of