Genetics and Genomics of Obesity

Genetics and Genomics of Obesity

Genetics and Genomics of Obesity: Current Status Claude Bouchard Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisi...

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Genetics and Genomics of Obesity: Current Status Claude Bouchard Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA

I. Familial Risk Level and Heritability Coefficients ....................................... II. Scope of the Volume........................................................................... References .......................................................................................

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It is commonly recognized that the prevalence of overweight and obesity is increasing around the world and that the obese are becoming more severely obese. Current estimates suggest that there are more than one billion adults who are overweight or obese worldwide. Recognizing the threat associated with excess weight, the World Health Organization has identified overweight as one of the main risk factors for the overall burden of disease in the world and one of the top five in developed nations.1 There are four major classes of factors contributing to the ongoing epidemic of obesity, which is ultimately the result of widespread energy imbalance favoring storage of the energy surplus not expended. These four broad classes of factors can be labeled as follows: built environment, social environment, behavior, and biology.2 We have proposed before that the built environment (e.g., reliance on the automobile, building design, lack of safe sidewalks) and the social environment (e.g., advertising, pressure to consume) are such that the global environment has become ‘‘obesogenic’’ not only in developed countries but also in most developing areas of the world.3 As the concept implies, an obesogenic environment favors the adoption of obesogenic behavior (e.g., consumption of large-portion-size meals, high-fat diets, high sugar intake, many hours spent watching TV, playing video games, or sitting at a computer). Common sense suggests that the obesogenic environment and behavior are fueling the acute rise in the prevalence of overweight and obesity that the world is currently experiencing. However, a complete definition of the circumstances fueling this rise needs to incorporate the concept of biological predisposition as well. Progress in Molecular Biology and Translational Science, Vol. 94 DOI: 10.1016/S1877-1173(10)94001-5


Copyright 2010, Elsevier Inc. All rights reserved. 1877-1173/10 $35.00



A large body of research conducted in animal models and in humans over the past five decades has demonstrated beyond a shadow of a doubt that there are large individual differences in the propensity to gain weight in a variety of obesogenic conditions.4 Strong evidence has been found for the contention that, even though it is not the sole causal source, genetic variation has much to do with the risk of becoming obese, particularly severe obesity. Hundreds of research reports have dealt with the critical issue of finding the exact site of the biological vulnerability to obesity. However, it is fair to summarize that (a) there is no consensus on this topic as of yet for the common forms of obesity, although results from the genome-wide association studies suggest that the regulation of appetite and satiety is playing a particularly critical role, (b) there are multiple paths to excessive energy storage involving several organs and systems, and (c) there is considerable heterogeneity in the biological determinants of excessive weight gain among individuals of a given species.

I. Familial Risk Level and Heritability Coefficients It is commonly accepted that genetic differences among people play an important role in the risk of becoming obese, and the global evidence for the genetic contribution to obesity, as derived from genetic epidemiology models, has been reviewed elsewhere.4 A first line of evidence is the observation that single gene syndromic and nonsyndromic disorders account for as much as 5% of obesity cases worldwide. Heritability estimates are generally derived from pairs of identical and fraternal twins raised together (but in some studies raised apart), nuclear family members from two generations, and adopted offspring raised by foster parents (but occasionally with information on their biological parents). The large body of data available to date reveals that the magnitude of the heritability estimates varies substantially among these various designs, with the twin models generating the highest values and the adoption studies the lowest coefficients. Another line of evidence for the presence of a genetic component in adult BMI comes from the computation of the lambda coefficient or familial risk ratio.5 Few studies have dealt with the familial risk ratio of human obesity. Lee and collaborators have computed such a ratio for various levels of BMI in firstdegree relatives of probands in the World Health Organization classes of obesity.6 The familial risk was found to increase with the severity of obesity, reaching 5 and higher with BMI levels of 40 and more. This suggests that an adult with a father, mother, brother, or sister with a BMI of about 40 is about five times more at risk of becoming obese with a BMI of 40 or more compared



to individuals in the population who have only normal-weight first-degree relatives. Importantly, for a BMI level around 30, the familial risk is in the range of 2–3. Although the consensus among obesity scientists is that the genetic component of obesity is quite high (in the range of 50–90%), one should keep an open mind regarding the possibility that the heritability values are highly inflated. For instance, some studies have found much lower heritability levels for BMI. Among them are studies performed using partial-adoption and full-adoption designs7,8 and a report based on data aggregated from twins, nuclear families, and foster parents with adopted offspring.9 Fueling this debate is the surprising observation that with about 20 loci identified through genome-wide association studies,10 and with the predicted diminishing return in the effect size of the additional loci that may reach genome-wide significance in the presence of extraordinarily large sample sizes, only about 2% of the variance in BMI was accounted for.11 Ultimately, this issue will be resolved only with a better understanding of the genetic architecture of the predisposition to obesity, that is, when all the loci have been properly identified and documented and when the role of epigenetic events in the genetic risk have been defined. We are of the view that the current global obesity epidemic is fueled by a changing social and physical environment that encourages consumption and discourages expenditure of energy, behaviors that are poorly compatible with the genome that we have inherited.2 Will it ever be possible to take advantage of the advances in our understanding of the genetic basis of obesity in order to identify the individuals at risk of becoming obese (not the single gene obesity cases in which such a screening is already widely recognized as a major advance) before they gain a large amount of body weight and adiposity? There is as of yet no consensus on this eventuality. In the meantime, the advances that have been made and will continue to accrue regarding our understanding of the genetic architecture of obesity will undoubtedly lead to new and exciting research on the biology and behavior of energy balance regulation.

II. Scope of the Volume In this volume of Progress in Molecular Biology and Translational Science, we review the latest evidence for the contribution of genetic factors to the risk of obesity. Genes and pathways potentially involved and the behavior that they influence are explored. The role of genetic variation in white and brown adipose tissue biology, excess adipose tissue mass, syndromic and nonsyndromic obesity cases, and lipodystrophies is highlighted. The case is made that a



systems biology approach is needed in order to arrive at a comprehensive and integrative solution to the enormously complex question of the biological predisposition to obesity. This volume also discusses our current understanding of the genetic basis of eating disorders, eating behavior, and physical activity level. The results of the findings from the recent genome-wide association studies of obesity and of epigenetic studies are reviewed. Further, the role of genetic differences in the modulation of risk factors for common chronic diseases and morbidities in the presence of an obese state is introduced. The final chapter comments upon the translational opportunities from what we have learned in animal and human studies on the genetics of obesity. Chapter 2 by Thomas Drake from the University of California, Los Angeles, focuses on genes and pathways contributing to obesity from a systems biology perspective. Systems biology utilizes high-throughput data from multiple sources to develop models of biologic processes. The author argues that the increasing ability to generate high-throughput genetic, epigenetic, and transcriptomic data of various types will result in a greater reliance on systems approaches to better understand the processes by which genetic variation influences disease-related traits. In Chapter 3, Ingrid Dahlman and Peter Arner from the Karolinska Institute in Stockholm deal with the genetics of adipose tissue biology, with an emphasis on morphology and function. Adipose tissue morphology and lipolytic properties are thought to be influenced by strong genetic determinants. Polymorphisms in numerous adipose-expressed genes have been evaluated for association with relevant adipose tissue traits, including morphological traits, adipocyte lipolysis, adipogenesis and lipid storage markers, and circulating levels of adipose tissue-secreted hormones and adipokines. These genes and allelic effects are reviewed in this chapter. Leslie Kozak and Robert Koza from the Pennington Biomedical Research Center in Baton Rouge, Louisiana, discuss the genetics of brown adipose tissue in Chapter 4. Brown adipose tissue has evolved as a mechanism for heat production based upon uncoupling of mitochondrial oxidative phosphorylation. The development of brown adipocytes originates from two apparently independent pathways: one from muscle progenitor cells in the fetus leading to fully functional cells at birth, the other emerging in white fat depots at weaning. Although the latter regresses, it can be induced in adult mice upon adrenergic stimulation. Alleles at genetic loci in mice are associated with a 100-fold difference in brown adipocyte induction in white fat upon adrenergic stimulation. The recent surge of interest in human brown adipose tissue was brought about by technological advances allowing more accurate imaging of the tissue. Whether brown adipose tissue can be activated to enhance its energy expenditure potential is of great interest in obesity research and has spurred new studies of the biology of this tissue in humans.



Chapter 5 is devoted to single gene disorders. Philip Beales from the Institute of Child Health and Great Ormond Street Hospital for Children in London discusses the evidence for single defective genes that have been implicated in human obesity. These disorders are classified as nonsyndromic or syndromic obesity. Taking advantage of several monogenic disorders, researchers have identified and dissected key regulatory pathways of energy balance. Among them, defective alleles in LEP, LEPR, and MC4R have provided critical insights into the biology and behavior of human obesity. Matthew Lanktree, Christopher Johansen, Tisha Joy, and Robert Hegele from the University of Western Ontario develop the topic of human lipodystrophies in Chapter 6. Lipodystrophy defines a group of heterogeneous disorders characterized by selective or generalized atrophy of anatomical adipose tissue stores. Lipodystrophies can be acquired or inherited. The loss of the ability to store lipids in common adipose tissue depots can result in significant metabolic disorders. This review focuses on clinical characterization of a suspected lipodystrophy case, clinical manifestations, molecular findings and the pathogenic basis of different forms of lipodystrophy, therapeutic options for lipodystrophy patients, and genetic advances that may be helpful in the identification of new pathogenic mechanisms. Chapter 7 by Anthony Comuzzie, Paul Higgins, Saroja Voruganti, and Shelly Cole from the Southwest Foundation for Biomedical Research in San Antonio, Texas, discusses the various strategies for identifying genes contributing to human obesity. Recent findings from candidate gene, genome-wide linkage, and genome-wide association studies are reviewed, with an emphasis on strengths and weaknesses of the evidence. A large number of genes with small effect sizes is the most likely scenario to account for the genetic component of obesity. Uncovering all such genes requires very large cohorts and multiple replication studies. Such resources have been assembled, and the discovery process should deliver the panel of the most important genes and alleles in the not too distant future. The genetics of taste and smell is discussed by Danielle Reed and Antti Knaapila from the Monell Chemical Senses Center in Philadelphia in Chapter 8. The senses of taste and smell have evolved so that humans recognize the bitter taste of poisons and the sour taste and bad smell of spoiled foods. But food selection is influenced by more than avoiding the bad; it is also motivated by seeking the good, such as fat and sugar. Yet what constitutes the best food and drink is often a matter of opinion. Genetic studies in humans and experimental animals strongly suggest that the liking of sugar and fat is influenced by genotype. Some progress has been made in defining the genes and their alleles associated with the positive and negative aspects of food and flavor. This chapter provides a genetic and evolutionary perspective on food perception and preference.



In Chapter 9, Anke Hinney, Susann Scherag, and Johannes Hebebrand from the University of Duisburg-Essen in Germany focus on the genetics of anorexia nervosa and bulimia nervosa. A complex etiology encompassing environmental and genetic factors is common to eating disorders, and the evidence from twin and family studies suggests that there is a strong genetic component. However, candidate gene studies derived mainly from pathways associated with appetite and satiety in the brain have yielded very few positive results, and findings substantiated in meta-analyses are scant. Genome-wide linkage approaches have been performed to identify genes with no a priori evidence for their relevance in eating disorders with limited success. Currently, there is high expectation in the field, as the results of the first genome-wide association study of eating disorders should be available soon. Trudy Moore-Harrison and Timothy Lightfoot from the University of North Carolina at Charlotte report on the genetics of physical activity level in Chapter 10. Physical activity level is a complex, multifactorial behavior with multiple determinants. A sedentary mode of life is a risk factor for gaining weight and becoming obese, and human studies and animal models have indicated that genetic differences play a role in the inclination to be active or sedentary. Several genomic quantitative trait loci have been suggestively associated with physical activity level in both rodent and human studies. Some reports have revealed pleiotropic effects between the genetic determinants of physical activity level and body weight regulation. Early results from genomewide association studies suggest that it may be possible to identify the genes and sequence variants associated with the propensity to be physically active. Chapter 11 deals with epigenetic events and obesity and was written by Javier Campio´n, Fermin Milagro, and Alfredo Martı´nez from the University of Navarra in Pamplona, Spain. Epigenetics, defined as the study of heritable changes in gene expression that occur without a change in the DNA sequence, has emerged as a potentially important determinant of obesity. There is suggestive evidence to the effect that DNA methylation profile and histone epigenetic modifications could be helpful in the prediction of obesity risk, as well as in the ability to gain or lose weight. In this chapter, the concept of epiobesogenes is introduced and defined as a set of obesogenes that are potentially exerting their deleterious effects as a result of epigenetic events. The importance of maternal nutrition and early postnatal nutritional circumstances with respect to epigenetic events is highlighted. In Chapter 12, Joshua Lewis and Alan Shuldiner from the University of Maryland School of Medicine address the critical issue of whether the metabolic complications of obesity are precipitated by genetic factors. The mechanisms linking obesity to its clinical outcomes are complex and not fully understood. Among potential causal pathways, attention has been devoted to insulin resistance and hyperinsulinemia, hypertriglyceridemia, dysfunctional



adipose tissue with abnormal secretion of adipokines, elevated inflammatory markers, ectopic lipid deposition in skeletal muscle, liver, and other organs, and others. Since not all obese individuals develop the metabolic complications of obesity, attempts to identify the genetic predisposition to excess adiposity have been undertaken, with an emphasis on candidate genes. These genes are reviewed in detail in this chapter. The requirements for such studies to be successful in the future are also defined. In the final contribution to this volume (Chapter 13), Craig Warden and Janis Fisler from the University of California, Davis, ask whether what we have learned from animal and human genetic studies of obesity can be translated into practical applications. Genetic testing is already a reality for several single gene disorders causing obesity. A central issue is determining the conditions under which genotype information would be useful for preventing or treating the common form of obesity. Currently, family history is more predictive than specific genes and sequence variants for defining the risk of obesity, but individual testing could, in the future, guide obesity therapy and perhaps even public health policy designed to prevent excessive weight gain. A potentially serious ethical problem relates to prenatal testing, assuming that obesity gene screening tests will eventually become available. In summary, human biology has been shaped by the ability to survive famines, to gorge during periods of food abundance, to adapt to cold or hot climates, to hunt or fight predators, and to escape from or attack adversaries, as well as by the advantages conferred by a large or a small body size, by the immune response capacity, by random allele selection, by sexual selection, and by other forces and events.2 Identifying the genes and alleles that were selected for during our evolutionary journey constitutes an enormously complex undertaking. However, the fundamental principle remains valid: if a predisposition to obesity exists, and it seems to be the case as suggested by a reasonable body of data, it is faithfully recorded in our genome, and it is potentially modulated by epigenetic events currently under intensive investigation. Nonetheless, if it is not in our genome, it is not part of the inherited vulnerability that we observe today in some human lineages and family lines.

References 1. World Health Organization. The global burden of disease 2004 update. Geneva: World Health Organization; 2008. 2. Bouchard C. The biological predisposition to obesity: beyond the thrifty gene scenario. Int J Obes 2007;31:1337–9. 3. Lakka HM, Bouchard C. Etiology of obesity. In: Buchwald H, Cowan GSM, Pories WJ, editors. Surgical management of obesity. Philadelphia: Saunders; 2006. p. 18–28 [chapter 3]. 4. Loos RJF, Bouchard C. Obesity—is it a genetic disorder? J Intern Med 2003;254:401–25.



5. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 1990;46:222–8. 6. Lee JH, Reed DR, Price RA. Familial risk ratios for extreme obesity: implications for mapping human obesity genes. Int J Obes Relat Metab Disord 1997;21:935–40. 7. Sorensen TIA, Stunkard AJ. Overview of the adoption studies. In: Bouchard C, editor. The genetics of obesity. Boca Raton, FL: CRC Press; 1994. p. 49–63. 8. Stunkard AJ, Sørensen TI, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986;314:193–8. 9. Bouchard C, Pe´russe L, Leblanc C, Tremblay A, The´riault G. Inheritance of the amount and distribution of human body fat. Int J Obes 1988;12:205–15. 10. Li S, Zhao JH, Luan J, Luben RN, Rodwell SA, Khaw KT, et al. Cumulative effects and predictive value of common obesity–susceptibility variants identified by genome-wide association studies. Am J Clin Nutr 2010;91:184–90. 11. Bouchard C. Defining the genetic architecture of the predisposition to obesity: a challenging but not insurmountable task. Am J Clin Nutr 2010;91:5–6.