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GeroScience Aug 2023Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed...
Frailty is an aging-related clinical phenotype defined as a state in which there is an increase in a person's vulnerability for dependency and/or mortality when exposed to a stressor. While underlying mechanisms leading to the occurrence of frailty are complex, the importance of genetic factors has not been fully investigated. We conducted a large-scale genome-wide association study (GWAS) of frailty, as defined by the five criteria (weight loss, exhaustion, physical activity, walking speed, and grip strength) captured in the Fried Frailty Score (FFS), in 386,565 European descent participants enrolled in the UK Biobank (mean age 57 [SD 8] years, 208,481 [54%] females). We identified 37 independent, novel loci associated with the FFS (p < 5 × 10), including seven loci without prior described associations with other traits. The variants associated with FFS were significantly enriched in brain tissues as well as aging-related pathways. Our post-GWAS bioinformatic analyses revealed significant genetic correlations between FFS and cardiovascular-, neurological-, and inflammation-related diseases/traits, and subsequent Mendelian Randomization analyses identified causal associations with chronic pain, obesity, diabetes, education-related traits, joint disorders, and depressive/neurological, metabolic, and respiratory diseases. The GWAS signals were replicated in the Health and Retirement Study (HRS, n = 9,720, mean age 73 [SD 7], 5,582 [57%] females), where the polygenic risk score built from UKB GWAS was significantly associated with the FFS in HRS individuals (OR per SD of the score 1.27, 95% CI 1.22-1.31, p = 1.3 × 10). These results provide new insight into the biology of frailty by comprehensively evaluating its genetic architecture.
Topics: Female; Humans; Aged; Male; Genome-Wide Association Study; Frailty; Obesity; Phenotype; Inflammation
PubMed: 36928559
DOI: 10.1007/s11357-023-00771-z -
Journal of Clinical Medicine Feb 2024Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can... (Review)
Review
Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.
PubMed: 38546831
DOI: 10.3390/jcm13051347 -
Obesity Pillars Sep 2024Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality,... (Review)
Review
BACKGROUND
Obesity is a multifactorial neurohormonal disease that results from dysfunction within energy regulation pathways and is associated with increased morbidity, mortality, and reduced quality of life. The most common form is polygenic obesity, which results from interactions between multiple gene variants and environmental factors. Highly penetrant monogenic and syndromic obesities result from rare genetic variants with minimal environmental influence and can be differentiated from polygenic obesity depending on key symptoms, including hyperphagia; early-onset, severe obesity; and suboptimal responses to nontargeted therapies. Timely diagnosis of monogenic or syndromic obesity is critical to inform management strategies and reduce disease burden. We outline the physiology of weight regulation, role of genetics in obesity, and differentiating characteristics between polygenic and rare genetic obesity to facilitate diagnosis and transition toward targeted therapies.
METHODS
In this narrative review, we focused on case reports, case studies, and natural history studies of patients with monogenic and syndromic obesities and clinical trials examining the efficacy, safety, and quality of life impact of nontargeted and targeted therapies in these populations. We also provide comprehensive algorithms for diagnosis of patients with suspected rare genetic causes of obesity.
RESULTS
Patients with monogenic and syndromic obesities commonly present with hyperphagia (ie, pathologic, insatiable hunger) and early-onset, severe obesity, and the presence of hallmark characteristics can inform genetic testing and diagnostic approach. Following diagnosis, specialized care teams can address complex symptoms, and hyperphagia is managed behaviorally. Various pharmacotherapies show promise in these patient populations, including setmelanotide and glucagon-like peptide-1 receptor agonists.
CONCLUSION
Understanding the pathophysiology and differentiating characteristics of monogenic and syndromic obesities can facilitate diagnosis and management and has led to development of targeted pharmacotherapies with demonstrated efficacy for reducing body weight and hunger in the affected populations.
PubMed: 38766314
DOI: 10.1016/j.obpill.2024.100110 -
Genome Biology Mar 2023Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a...
BACKGROUND
Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated.
RESULTS
We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes.
CONCLUSIONS
Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.
Topics: Mice; Animals; Phosphorylation; Diabetes Mellitus, Type 2; Multiomics; Quantitative Trait Loci; Peptides
PubMed: 36944993
DOI: 10.1186/s13059-023-02892-2 -
Maedica Sep 2022Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food...
Obesity is defined by an imbalance between energy expenditure and energy consumption. Presently, it is considered a global problem because people are consuming junk food and doing less physical activity in every country of the world. It is all due to sedentary life style. The currently available drugs for the treatment of obesity are not giving satisfactory results as they have many adverse effects along with rebound obesity complications. To evaluate new drug in pre-clinical study, we need to have better supportive animal models. Obesity can be induced by giving drugs, fat food, surgical procedures, and by genetic modifications. In the present review, various obesity induced models have been explained to evaluate new compounds. In experimental animal models, monogenic and polygenic obesity models have been reviewed, with a proper pathway to prepare new drugs being given. While in the existing models, genetic obesity models were not explained so far, here genetic engineered transgenic models were described to evaluate new anti-obesity drugs. This short review on chemically and surgically induced obesity models aimed to provide a better understanding of the experimental design of obesity.
PubMed: 36540593
DOI: 10.26574/maedica.2022.17.3.706 -
Blood Advances Sep 2023Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous... (Meta-Analysis)
Meta-Analysis
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.
Topics: Male; Humans; Female; Depressive Disorder, Major; Venous Thromboembolism; Bipolar Disorder; Schizophrenia; Risk Factors
PubMed: 37399490
DOI: 10.1182/bloodadvances.2023010562 -
Nutrients Jun 2023Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese-650 million adults, 340 million adolescents, and 39 million children.... (Review)
Review
Obesity is a common, serious, and costly disease. More than 1 billion people worldwide are obese-650 million adults, 340 million adolescents, and 39 million children. The WHO estimates that, by 2025, approximately 167 million people-adults and children-will become less healthy because they are overweight or obese. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer. These are among the leading causes of preventable, premature death. The estimated annual medical cost of obesity in the United States was nearly $173 billion in 2019 dollars. Obesity is considered the result of a complex interaction between genes and the environment. Both genes and the environment change in different populations. In fact, the prevalence changes as the result of eating habits, lifestyle, and expression of genes coding for factors involved in the regulation of body weight, food intake, and satiety. Expression of these genes involves different epigenetic processes, such as DNA methylation, histone modification, or non-coding micro-RNA synthesis, as well as variations in the gene sequence, which results in functional alterations. Evolutionary and non-evolutionary (i.e., genetic drift, migration, and founder's effect) factors have shaped the genetic predisposition or protection from obesity in modern human populations. Understanding and knowing the pathogenesis of obesity will lead to prevention and treatment strategies not only for obesity, but also for other related diseases.
Topics: Adult; Child; Adolescent; Humans; United States; Diabetes Mellitus, Type 2; Obesity; Overweight; Body Weight; Life Style
PubMed: 37375686
DOI: 10.3390/nu15122782 -
European Journal of Medical Genetics Mar 2022Obesity is a growing public health problem in many developed countries, although similar trends are increasingly being described in some developing nations. The genetic... (Review)
Review
Obesity is a growing public health problem in many developed countries, although similar trends are increasingly being described in some developing nations. The genetic underpinnings of obesity continue to arouse increasing research interests, investigations, and discussions. The recent advances in next generation sequencing technologies have shed some more light on the diverse monogenic and polygenic causes of obesity. Syndromic obesity due to chromosomal or monogenic defects has attendant co-morbidities, which may include neurodevelopmental delays, dysmorphism as well as organ-specific developmental anomalies. An improved understanding of the nature of neurodevelopmental challenges in syndromic obesity may pave the way for personalized dietary and physical activity management approaches. This review article describes the clinical and molecular genetic aspects of obesity-related syndromes and the associated neurodevelopmental disabilities. The potential opportunities for individualized nutrigenomic managements of syndromic obesity are also highlighted.
Topics: High-Throughput Nucleotide Sequencing; Humans; Intellectual Disability; Obesity; Syndrome
PubMed: 35085835
DOI: 10.1016/j.ejmg.2022.104443 -
Neuroscience and Biobehavioral Reviews Feb 2020Obesity has dramatically increased during the last decades and is currently one of the most serious global health problems. We present a hypothesis that obesity is a... (Review)
Review
Obesity has dramatically increased during the last decades and is currently one of the most serious global health problems. We present a hypothesis that obesity is a neuro-behavioral disease having a strong genetic background mediated largely by eating behavior and is sensitive to the macro-environment; we study this hypothesis from the perspective of genetic research. Genetic family and genome-wide-association studies have shown well that body mass index (BMI, kg/m) is a highly heritable and polygenic trait. New genetic variation of BMI emerges after early childhood. Candidate genes of BMI notably express in brain tissue, supporting that this new variation is related to behavior. Obesogenic environments at both childhood family and societal levels reinforce the genetic susceptibility to obesity. Genetic factors have a clear influence on macro-nutrient intake and appetite-related eating behavior traits. Results on the gene-by-diet interactions in obesity are mixed, but emerging evidence suggests that eating behavior traits partly mediate the effect of genes on BMI. However, more rigorous prospective study designs controlling for measurement bias are still needed.
Topics: Body Mass Index; Feeding Behavior; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Multifactorial Inheritance; Obesity
PubMed: 31959301
DOI: 10.1016/j.neubiorev.2019.12.012 -
Molecular Psychiatry Mar 2021There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this...
There is an extensive body of literature linking ADHD to overweight and obesity. Research indicates that impulsivity features of ADHD account for a degree of this overlap. The neural and polygenic correlates of this association have not been thoroughly examined. In participants of the IMAGEN study, we found that impulsivity symptoms and body mass index (BMI) were associated (r = 0.10, n = 874, p = 0.014 FWE corrected), as were their respective polygenic risk scores (PRS) (r = 0.17, n = 874, p = 6.5 × 10 FWE corrected). We then examined whether the phenotypes of impulsivity and BMI, and the PRS scores of ADHD and BMI, shared common associations with whole-brain grey matter and the Monetary Incentive Delay fMRI task, which associates with reward-related impulsivity. A sparse partial least squared analysis (sPLS) revealed a shared neural substrate that associated with both the phenotypes and PRS scores. In a last step, we conducted a bias corrected bootstrapped mediation analysis with the neural substrate score from the sPLS as the mediator. The ADHD PRS associated with impulsivity symptoms (b = 0.006, 90% CIs = 0.001, 0.019) and BMI (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. The BMI PRS associated with BMI (b = 0.014, 95% CIs = 0.003, 0.033) and impulsivity symptoms (b = 0.009, 90% CIs = 0.001, 0.025) via the neuroimaging substrate. A common neural substrate may (in part) underpin shared genetic liability for ADHD and BMI and the manifestation of their (observable) phenotypic association.
Topics: Attention Deficit Disorder with Hyperactivity; Body Mass Index; Humans; Impulsive Behavior; Multifactorial Inheritance; Reward
PubMed: 31227801
DOI: 10.1038/s41380-019-0444-y