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Cell Apr 2019Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be...
Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment.
Topics: Adolescent; Body Mass Index; Body Weight; Child; Databases, Factual; Female; Genome-Wide Association Study; Humans; Infant, Newborn; Longitudinal Studies; Male; Middle Aged; Multifactorial Inheritance; Obesity; Risk Factors; Severity of Illness Index
PubMed: 31002795
DOI: 10.1016/j.cell.2019.03.028 -
Molecular Diagnosis & Therapy Dec 2020Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes... (Review)
Review
Obesity represents a major health burden to both developed and developing countries. Furthermore, the incidence of obesity is increasing in children. Obesity contributes substantially to mortality in the United States by increasing the risk for type 2 diabetes, cardiovascular-related diseases, and other comorbidities. Despite environmental changes over past decades, including increases in high-calorie foods and sedentary lifestyles, there is very clear evidence of a genetic predisposition to obesity risk. Childhood obesity cases can be categorized in one of two ways: syndromic or non-syndromic. Syndromic obesity includes disorders such as Prader-Willi syndrome, Bardet-Biedl syndrome, and Alström syndrome. Non-syndromic cases of obesity can be further separated into rarer instances of monogenic obesity and much more common forms of polygenic obesity. The advent of genome-wide association studies (GWAS) and next-generation sequencing has driven significant advances in our understanding of the genetic contribution to childhood obesity. Many rare and common genetic variants have been shown to contribute to the heritability in obesity, although the molecular mechanisms underlying most of these variants remain unclear. An important caveat of GWAS efforts is that they do not strictly represent gene target discoveries, rather simply the uncovering of robust genetic signals. One clear example of this is with progress in understanding the key obesity signal harbored within an intronic region of the FTO gene. It has been shown that the non-coding region in which the variant actually resides in fact influences the expression of genes distal to FTO instead, specifically IRX3 and IRX5. Such discoveries suggest that associated non-coding variants can be embedded within or next to one gene, but commonly influence the expression of other, more distal effector genes. Advances in genetics and genomics are therefore contributing to a deeper understanding of childhood obesity, allowing for development of clinical tools and therapeutic agents.
Topics: Child; Genetic Predisposition to Disease; Genetic Variation; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Pediatric Obesity; Risk Factors
PubMed: 33006084
DOI: 10.1007/s40291-020-00496-1 -
International Journal of Molecular... Sep 2022Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and... (Review)
Review
Obesity is a complex multifactorial disorder with genetic and environmental factors. There is an increase in the worldwide prevalence of obesity in both developed and developing countries. The development of genome-wide association studies (GWAS) and next-generation sequencing (NGS) has increased the discovery of genetic associations and awareness of monogenic and polygenic causes of obesity. The genetics of obesity could be classified into syndromic and non-syndromic obesity. Prader-Willi, fragile X, Bardet-Biedl, Cohen, and Albright Hereditary Osteodystrophy (AHO) syndromes are examples of syndromic obesity, which are associated with developmental delay and early onset obesity. Non-syndromic obesity could be monogenic, polygenic, or chromosomal in origin. Monogenic obesity is caused by variants of single genes while polygenic obesity includes several genes with the involvement of members of gene families. New advances in genetic testing have led to the identification of obesity-related genes. Leptin (), the leptin receptor (), proopiomelanocortin (), prohormone convertase 1 (), the melanocortin 4 receptor (), single-minded homolog 1 (), brain-derived neurotrophic factor (), and the neurotrophic tyrosine kinase receptor type 2 gene () have been reported as causative genes for obesity. NGS is now in use and emerging as a useful tool to search for candidate genes for obesity in clinical settings.
Topics: Brain-Derived Neurotrophic Factor; Genome-Wide Association Study; Humans; Leptin; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptor, trkB; Receptors, Leptin
PubMed: 36232301
DOI: 10.3390/ijms231911005 -
Cell Metabolism Mar 2017Except in rare cases, obesity tends to be a consequence of both an unhealthy lifestyle and a genetic susceptibility to gain weight. With more than 200 common genetic... (Review)
Review
Except in rare cases, obesity tends to be a consequence of both an unhealthy lifestyle and a genetic susceptibility to gain weight. With more than 200 common genetic variants identified, there is a growing interest in developing personalized preventive and treatment strategies to predict an individual's obesity risk. We review the literature on the prediction of obesity and show that models based on the established genetic variants have poorer predictive ability than traditional predictors, such as family history of obesity and childhood obesity. Current findings suggest that opportunities for precision medicine in common obesity may be limited.
Topics: Genetic Predisposition to Disease; Genetic Variation; Humans; Life Style; Multifactorial Inheritance; Obesity; Risk Factors
PubMed: 28273476
DOI: 10.1016/j.cmet.2017.02.013 -
Comptes Rendus Biologies Feb 2017Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and... (Review)
Review
Obesity and its related health complications is a major problem worldwide. Hypothalamus and their signalling molecules play a critical role in the intervening and coordination with energy balance and homeostasis. Genetic factors play a crucial role in determining an individual's predisposition to the weight gain and being obese. In the past few years, several genetic variants were identified as monogenic forms of human obesity having success over common polygenic forms. In the context of molecular genetics, genome-wide association studies (GWAS) approach and their findings signified a number of genetic variants predisposing to obesity. However, the last couple of years, it has also been noticed that alterations in the environmental and epigenetic factors are one of the key causes of obesity. Hence, this review might be helpful in the current scenario of molecular genetics of human obesity, obesity-related health complications (ORHC), and energy homeostasis. Future work based on the clinical discoveries may play a role in the molecular dissection of genetic approaches to find more obesity-susceptible gene loci.
Topics: Energy Metabolism; Genetic Predisposition to Disease; Genetics, Medical; Genome-Wide Association Study; Humans; Obesity
PubMed: 28089486
DOI: 10.1016/j.crvi.2016.11.007 -
Minerva Endocrinologica Sep 2020Obese or overweight people exceed one-third of the global population and obesity along with diabetes mellitus consist basic components of metabolic syndrome, both of... (Review)
Review
Obese or overweight people exceed one-third of the global population and obesity along with diabetes mellitus consist basic components of metabolic syndrome, both of which are known cardio-cerebrovascular risk factors with detrimental consequences. These data signify the pandemic character of obesity and the necessity for effective treatments. Substantial advances have been accomplished in preclinical research of obesity by using animal models, which mimic the human disease. In particular, rodent models have been widely used for many decades with success for the elucidation of the pathophysiology of obesity, since they share physiological and genetic components with humans and appear advantageous in their husbandry. The most representative rodents include the laboratory mouse and rat. Within this review, we attempted to consolidate the most widely used mice and rat models of obesity and highlight their strengths as well as weaknesses in a critical way. Our aim was to bridge the gap between laboratory facilities and patient's bed and help the researcher find the appropriate animal model for his/her obesity research. This tactful selection of the appropriate model of obesity may offer more translational derived results. In this regard, we included, the main diet induced models, the chemical/mechanical ones, as well as a selection of monogenic or polygenic models.
Topics: Animals; Diet; Disease Models, Animal; Humans; Metabolic Syndrome; Mice; Obesity; Rats; Rodentia
PubMed: 31738033
DOI: 10.23736/S0391-1977.19.03058-X -
Obesity Facts 2008The molecular genetic analysis of obesity has led to the identification of a limited number of confirmed major genes. While such major genes have a clear influence on... (Review)
Review
The molecular genetic analysis of obesity has led to the identification of a limited number of confirmed major genes. While such major genes have a clear influence on the development of the phenotype, the underlying mutations are however (extremely) infrequent and thus of minor clinical importance only. The genetic predisposition to obesity must thus be polygenic; a number of such variants should be found in most obese subjects; however, these variants predisposing to obesity are also found in normal weight and even lean individuals. Therefore, a polygene can only be identified and validated by statistical analyses: the appropriate gene variant (allele) occurs more frequently in obese than in non-obese subjects. Each single polygene makes only a small contribution to the development of obesity. The 103Ile allele of the Val103Ile single nucleotide polymorphism (SNP) of the melanocortin-4 receptor gene (MC4R) was the first confirmed polygenetic variant with an influence on the body mass index (BMI); the more common Val103 allele is more frequent in obese individuals. As determined in a recent, large-scaled meta-analysis the effect size of this allele on mean BMI was approximately -0.5 kg/m(2). The first genome-wide association study (GWA) for obesity, based on approximately 100,000 SNPs analyzed in families of the Framingham study, revealed that a SNP in the proximity of the insulin-induced gene 2 (INSIG2) was associated with obesity. The positive result was replicated in independent samples; however, some other study groups detected no association. Currently, a meta-analysis is ongoing; its result will contribute to the evaluation of the importance of the INSIG2 polymorphism in body weight regulation. SNP alleles in intron 1 of the fat mass and obesity associated gene (FTO) confer the most relevant polygenic effect on obesity. In the first GWA for extreme early onset obesity we substantiated that variation in FTO strongly contributes to early onset obesity.
Topics: Genetic Linkage; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Obesity
PubMed: 20054160
DOI: 10.1159/000113935 -
Nature Reviews. Endocrinology Oct 2022Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the... (Review)
Review
Obesity is a multifactorial and complex disease that often manifests in early childhood with a lifelong burden. Polygenic and monogenic obesity are driven by the interaction between genetic predisposition and environmental factors. Polygenic variants are frequent and confer small effect sizes. Rare monogenic obesity syndromes are caused by defined pathogenic variants in single genes with large effect sizes. Most of these genes are involved in the central nervous regulation of body weight; for example, genes of the leptin-melanocortin pathway. Clinically, patients with monogenic obesity present with impaired satiety, hyperphagia and pronounced food-seeking behaviour in early childhood, which leads to severe early-onset obesity. With the advent of novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features. Likewise, patients with obesity associated with hypothalamic damage or other forms of syndromic obesity involving energy regulatory circuits could benefit from these novel pharmacological treatment options. Early identification of patients affected by syndromic obesity will lead to appropriate treatment, thereby preventing the development of obesity sequelae, avoiding failure of conservative treatment approaches and alleviating stigmatization of patients and their families.
Topics: Child, Preschool; Genetic Predisposition to Disease; Humans; Hyperphagia; Leptin; Melanocortins; Obesity; Phenotype; Receptors, Leptin
PubMed: 35902734
DOI: 10.1038/s41574-022-00716-0 -
Nutrients Mar 2023Overweight and obesity in childhood and adolescence represents one of the most challenging public health problems of our century owing to its epidemic proportions and... (Review)
Review
Overweight and obesity in childhood and adolescence represents one of the most challenging public health problems of our century owing to its epidemic proportions and the associated significant morbidity, mortality, and increase in public health costs. The pathogenesis of polygenic obesity is multifactorial and is due to the interaction among genetic, epigenetic, and environmental factors. More than 1100 independent genetic loci associated with obesity traits have been currently identified, and there is great interest in the decoding of their biological functions and the gene-environment interaction. The present study aimed to systematically review the scientific evidence and to explore the relation of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with changes in body mass index (BMI) and other measures of body composition in children and adolescents with obesity, as well as their response to lifestyle interventions. Twenty-seven studies were included in the qualitative synthesis, which consisted of 7928 overweight/obese children and adolescents at different stages of pubertal development who underwent multidisciplinary management. The effect of polymorphisms in 92 different genes was assessed and revealed SNPs in 24 genetic loci significantly associated with BMI and/or body composition change, which contribute to the complex metabolic imbalance of obesity, including the regulation of appetite and energy balance, the homeostasis of glucose, lipid, and adipose tissue, as well as their interactions. The decoding of the genetic and molecular/cellular pathophysiology of obesity and the gene-environment interactions, alongside with the individual genotype, will enable us to design targeted and personalized preventive and management interventions for obesity early in life.
Topics: Adolescent; Child; Humans; Pediatric Obesity; Overweight; Body Mass Index; Genotype; Polymorphism, Single Nucleotide
PubMed: 36986146
DOI: 10.3390/nu15061416 -
The Journal of Steroid Biochemistry and... Sep 2018Polycystic ovary syndrome (PCOS) is an endocrine disorder, afflicting females of reproductive age. This syndrome leads to infertility, insulin resistance, obesity, and... (Review)
Review
Polycystic ovary syndrome (PCOS) is an endocrine disorder, afflicting females of reproductive age. This syndrome leads to infertility, insulin resistance, obesity, and cardiovascular problems, including a litany of other health issues. PCOS is a polygenic, polyfactorial, systemic, inflammatory, dysregulated steroid state, autoimmune disease, manifesting largely due to lifestyle errors. The advent of biochemical tests and ultrasound scanning has enabled the detection of PCOS in the affected females. Subsequently, a huge amount of insight on PCOS has been garnered in recent times. Interventions like oral contraceptive pills, metformin, and hormone therapy have been developed to bypass or reverse the ill effects of PCOS. However, lifestyle correction to prevent aberrant immune activation and to minimize the exposure to inflammatory agents, appears to be the sustainable therapy of PCOS. This holistic review with multiple hypotheses might facilitate to devise better PCOS management approaches.
Topics: Endocrine System; Female; Humans; Inflammation; Insulin Resistance; Life Style; Obesity; Polycystic Ovary Syndrome
PubMed: 29678491
DOI: 10.1016/j.jsbmb.2018.04.008