Genetics of human obesity: lessons from mouse models and candidate genes

Obesity is a common disorder with potentially serious negative implications on health and quality of life and a rising prevalence worldwide, warranting effective treatments. The disorder runs in families, and important knowledge is expected to follow the identification of human obesity genes. Although statistical analysis of inheritance of obesity in humans suggests a large genetic component in obesity, up to 80%, few actual obesity genes have been identified so far. However, a number of obesity causing genes have successfully been cloned from rodents with monogenic forms of obesity, and it is probable that new knowledge in the field of human obesity will result from these findings.     

Genetics of Diabetes

Reviews in Endocrine and Metabolic Disorders -     

Genetics of osteoporosis in Chinese

Osteoporosis is a common skeletal disease characterized by low bone mineral density (BMD) and deterioration in bone microarchitecture, resulting in increased bone fragility and susceptibility to fractures. As a complex disease, it is determined by both genetic and environmental factors, as well as their interactive effects. Studies have suggested that different genetic determinants may be involved in different ethnic groups. In this paper, we reviewed the genetic studies of osteoporosis in A Chinese population, focusing on the genes affecting BMD, a surrogate phenotype of osteoporosis.     

Genetics of human obesity

Obesity is a multifactorial condition. Environmental risk factors related to a sedentary life-style and unlimited access to food apply constant pressure in subjects with a genetic predisposition to gain weight. The fact that genetic defects can result in human obesity has been unequivocally established over the past 3 years with the identification of the genetic defects responsible for different monogenic forms of human obesity: the leptin, leptin receptor, pro-opiomelanocortin, pro-hormone convertase-1 and melanocortin-4 receptor genes. The common forms of obesity are, however, polygenic. The examination of specific genes for involvement in the susceptibility to common obesity has not yet yielded convincing results. Approaches involving the candidate genes and the positional cloning of major obesity-linked regions (state-of-the-art future prospects) will be discussed.     

Genetics of human obesity

BACKGROUND: Both genetic and environmental aspects are recognized in the obesity field but we are not able to elucidate multiple genes and gene-environment interactions with the present resources and tools used in the study of this complex disease. The purpose of this paper is to present some examples of the knowledge acquired in the field of obesity genetics and the new ongoing tools and developments that aim at studying the contribution of genes to obesity and their response to environmental changes. MAIN POINTS: In rare cases of monogenic obesities, genetic tools have proved extremely powerful for identifying the genes responsible and for defining new syndromes. However, in common obesity, most studies include the search for genotype-phenotype associations without taking into account the influence of environment (diet, sedentary lifestyle) in the relationship. Among the limitations to this integrated approach, one can cite the difficulty of having large enough samples as well as biocomputing tools that are still in their infancy for accessing the question of multiple interactions with no "a priori hypotheses". This picture will probably change rapidly in the future. PERSPECTIVE: Large databases and DNA and biological sample banks will be available with updated environmental information and precise phenotypes thanks especially to European working groups. The capacity for studying multiple genes at once at the DNA or RNA levels is rapidly growing. Finally, tremendous progress in biocomputing will allow the integration of information from different sources (i.e. environment, phenotype, genotype, gene expression) and thus improve our ability to deal with complexity.     

Ethnic and population differences in the genetic predisposition to human obesity

Obesity rates have escalated to the point of a global pandemic with varying prevalence across ethnic groups. These differences are partially explained by lifestyle factors in addition to genetic predisposition to obesity. This review provides a comprehensive examination of the ethnic differences in the genetic architecture of obesity. Using examples from evolution, heritability, admixture, monogenic and polygenic studies of obesity, we provide explanations for ethnic differences in the prevalence of obesity. The debate over definitions of race and ethnicity, the advantages and limitations of multi‐ethnic studies and future directions of research are also discussed. Multi‐ethnic studies have great potential to provide a better understanding of ethnic differences in the prevalence of obesity that may result in more targeted and personalized obesity treatments.     

Genetics of Osteoporosis

Reviews in Endocrine and Metabolic Disorders -     

FTO: the first gene contributing to common forms of human obesity

Genome‐wide association, the latest gene‐finding strategy, has led to the first major success in the field of obesity genetics with the discovery of FTO (fat mass and obesity associated gene) as an obesity–susceptibility gene. A cluster of variants in the first intron of FTO showed a strong and highly significant association with obesity‐related traits in three independent genome‐wide association studies, a finding that has been replicated in several other studies including adults and children of European descent. Homozygotes for the risk allele weigh on average 3–4 kg more and have a 1.67‐fold increased risk of obesity compared with those who did not inherit a risk allele. We are still at an early stage in our understanding of the pathways through which FTO confers to increased obesity risk. Studies in humans and rodents have suggested a central role for FTO through regulation of food intake, whereas others have proposed a peripheral role through an effect on lipolytic activity in adipose tissue. There is no doubt that many more obesity–susceptibility loci remain to be discovered. Progress on this front will therefore require major collaborative efforts and pooling of compatible datasets. We stand to learn a lot about the genetic architecture of human obesity in the coming years. The expectations are high but many challenges remain. Among the latter, translating new advances into useful guidelines for prevention and treatment of obesity will be the most demanding.     

Genetics of Coronary Artery Disease: An Update

In 2007, the first genetic risk variant, 9p21, was simultaneously discovered by two independent groups. 9p21 increases the risk of coronary artery disease in individuals with premature heart disease by twofold, and in the overall population the heterozygote is associated with a 25% increased risk and the homozygote with a 50% increased risk. It is of note that the risk mediated by 9p21 is independent of known risk factors. Since then, with the development of new technologies and the international consortium of CARDIoGRAM, there is now a total of 50 genetic risk variants confirmed and replicated for CAD. Of these 50, 35 mediate their risk by unknown mechanisms, indicating that the pathogenesis of atherosclerosis and myocardial infarction is due to additional factors as yet unknown. The role of genetic risk factors in the management of CAD is yet to be determined. Since many of them are independent of known risk factors, the genetic risk will in the future have to be incorporated into the guidelines, which recommend the target level of plasma LDL-C to be achieved based on the number of risk factors.     

Genetics in primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models.     

Adrenoceptor genes in human obesity

The genes causing obesity in rodent models have been characterized, but do not seem to be important for human obesity. Recently the putative association between obesity and polymorphism in human beta-adrenergic receptor genes have been studied intensely in the light of the important role of these receptors in the regulation of energy mobilization and utilization. A polymorphism (Trp64Arg) in the beta3-adrenergic receptor gene is associated with obesity (relative risk approximately 2) in some but not all investigations on Caucasian and Japanese populations. When expressed in artificial cell systems, the polymorphism is associated with alterations of the beta -adrenoceptor. The genetic allele variance influences also the native receptor function when measured in isolated human fat cells. The human beta2-adrenoceptor gene shows a high degree of polymorphism. The role of beta2-receptor gene polymorphism for obesity has so far only been investigaed in women. A Gln27Glu variant is markedly associated with obesity with a relative risk for obesity of approximately 7 and odds ratio of approximately 10. Women who are homozygous for 27Glu have approximately 20 kg higher fat mass than controls. Thus, polymorphism in genes coding for different beta-adrenoceptor subtypes may be important for the development of human obesity.     

Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations

In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), body weight, height and body mass index (BMI) were evaluated as risk factors. Additionally, the joint effect of obesity together with oral contraceptive use and prothrombotic mutations on the risk of venous thrombosis were analysed. Three-thousand eight-hundred and thirty-four patients with a first venous thrombosis and 4683 control subjects were included, all non-pregnant and without active malignancies. Relative to those with a normal BMI (<25 kg/m(2)), overweight (BMI > or = 25 and BMI < 30 kg/m(2)) increased the risk of venous thrombosis 1.7-fold [odds ratio (OR)(adj(age and sex)) 1.70, 95% confidence interval (CI) 1.55-1.87] and obesity (BMI > or = 30 kg/m(2)) 2.4-fold (OR(adj) 2.44, 95% CI 2.15-2.78). An increase in body weight and body height also individually increased thrombotic risk. Obese women who used oral contraceptives had a 24-fold higher thrombotic risk (OR(adj) 23.78, 95% CI 13.35-42.34) than women with a normal BMI who did not use oral contraceptives. Relative to non-carriers of normal BMI, the joint effect of factor V Leiden and obesity led to a 7.9-fold increased risk (OR(adj) 7.86, 95% CI 4.70-13.15); for prothrombin 20210A this was a 6.6-fold increased risk (OR(adj) 6.58, 95% CI 2.31-18.69). Body height, weight and obesity increase the risk of venous thrombosis, especially obesity in women using oral contraceptives.     

Genetics of coronary artery disease in the post-GWAS era

During the past decade, genome-wide association studies (GWAS) have transformed our understanding of many heritable traits. Three recent large-scale GWAS meta-analyses now further markedly expand the knowledge on coronary artery disease (CAD) genetics in doubling the number of loci with genome-wide significant signals. Here, we review the unprecedented discoveries of CAD GWAS on low-frequency variants, underrepresented populations, sex differences and integrated polygenic risk. We present the milestones of CAD GWAS and post-GWAS studies from 2007 to 2021, and the trend in identification of variants with smaller odds ratio by year due to the increasing sample size. We compile the 321 CAD loci discovered thus far and classify candidate genes as well as distinct functional pathways on the road to indepth biological investigation and identification of novel treatment targets. We draw attention to systems genetics in integrating these loci into gene regulatory networks within and across tissues. We review the traits, biomarkers and diseases scrutinized by Mendelian randomization studies for CAD. Finally, we discuss the potentials and concerns of polygenic scores in predicting CAD risk in patient care as well as future directions of GWAS and post-GWAS studies in the field of precision medicine.     

Diagnosis and management of hypertension in obesity

Cardiovascular risk in a patient with obesity hypertension increases with the extent of risk factor clustering. It is therefore important to determine the global risk of a patient with hypertension rather than to focus solely on blood pressure. Every hypertensive should be screened for other than blood pressure risk factors, target organ damage and concomitant diseases or accompanying clinical conditions. Assessment of blood pressure and target organ damage might be more difficult in obese hypertensives than in normal-weight patients. Intensive lifestyle interventions can reduce weight, and decrease blood pressure and cardiovascular risk in obese hypertensive patients. Current guidelines do not provide specific recommendation for pharmacological management of the hypertensive patients with obesity. Recent trials have consistently shown that therapy involving beta-blockers and diuretics may induce more new-onset diabetes compared with other combination therapies. Several lines of evidence suggest that anti-hypertensive agents that block the renin-angiotensin system may be especially beneficial in treating obese hypertensive patients. Hypertension management in obese individuals is complicated by poorer response to treatment, and the increased need for multiple medications. It is important to consider obstructive sleep apnoea in the differential diagnosis of hypertensive patients who respond poorly to combination therapy with anti-hypertensive medications.     

Genetics of obesity

Animal models and family studies led to the identification ofcases of rare monogenic forms of human obesity. Rare Mendelian syndromes as Prader-Willi syndrome and Bardet-Biedl syndrome represent cases of genetically determined obesity. Genome wide linkage and classical candidate gene studies were in general unsuccessful concerning the identification of genes of common obesity. On the other hand, genome-wide association studies (GWAS) were found to be effective, as also variants with only a minor effect have been detected. Seventeen polygenic variants influencing body weight regulation were clearly confirmed. It is assumed that more of these variants exist and therefore they might be identified in near future by GWAS. It is possible that the size effect of some variants can be within few grams of body weight. In order to detect variants with small effect there is a need of meta-analyses based on hundreds of thousands of individuals. Newly identified variants result in an increase of 0.06-0.33 kg/m2 of BMI per allele. In an adult of an average height of 170cm, it corresponds to 173-954 g per risk allele. It was estimated that subjects carrying 13 or more risk alleles were on average 1.46 body mass index units heavier (representing 3.7-4.7 kg) than carriers of less than three risk alleles. Further research should be focused on a gene-gene interaction. An interaction ofgene and environment should be statistically analyzed in adequate proband cohorts. If we are able to identify a large number of risk variants, the predisposition to a certain disease could be predicted. Currently a detailed family history has more predictive power.     

The role of genes and environment in the etiology of PCOS

Both genes and the environment contribute to PCOS. Obesity, exacerbated by poor dietary choices and physical inactivity, worsens PCOS in susceptible individuals. The role of other environmental modifiers such as infectious agents or toxins are speculative. Phenotype confusion has characterized genetic studies of PCOS. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, the follistatin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin recept or gene (but not involving this gene), as it has been identified in two separate studies, and perhaps most importantly has not yet been refuted by larger studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. To date, no gene has been identified that causes or contributes substantially to the development of a PCOS phenotype.