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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 -
Current Cardiology Reports Oct 2020Obesity is a significant international public health epidemic with major downstream consequences on morbidity and mortality. While lifestyle factors contribute, there is... (Review)
Review
PURPOSE OF REVIEW
Obesity is a significant international public health epidemic with major downstream consequences on morbidity and mortality. While lifestyle factors contribute, there is an evolving understanding of genomic and metabolomic pathways involved with obesity and its relationship with cardiometabolic risk. This review will provide an overview of some of these important findings from both a biologic and clinical perspective.
RECENT FINDINGS
Recent studies have identified polygenic risk scores and metabolomic biomarkers of obesity and related outcomes, which have also highlighted biological pathways, such as the branched-chain amino acid (BCAA) pathway that is dysregulated in this disease. These biomarkers may help in personalizing obesity interventions and for mitigation of future cardiometabolic risk. A multifaceted approach is necessary to impact the growing epidemic of obesity and related diseases. This will likely include incorporating precision medicine approaches with genomic and metabolomic biomarkers to personalize interventions and improve risk prediction.
Topics: Amino Acids, Branched-Chain; Biomarkers; Cardiovascular Diseases; Genomics; Humans; Metabolomics; Obesity
PubMed: 33040225
DOI: 10.1007/s11886-020-01422-x -
Journal of Affective Disorders Sep 2022Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic... (Review)
Review
BACKGROUND
Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field.
METHODS
We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D.
RESULTS
The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk.
LIMITATIONS
The narrative nature of this review.
CONCLUSIONS
Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.
Topics: Bipolar Disorder; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Obesity; Polymorphism, Single Nucleotide
PubMed: 35780966
DOI: 10.1016/j.jad.2022.06.084 -
Metabolism: Clinical and Experimental Aug 2023The SREBP/SCAP/INSIG complex plays an essential role in SREBP activation and de novo lipogenesis. Whether the activation process is affected by hydroxysteroid 17-beta...
BACKGROUND
The SREBP/SCAP/INSIG complex plays an essential role in SREBP activation and de novo lipogenesis. Whether the activation process is affected by hydroxysteroid 17-beta dehydrogenase 6 (HSD17B6) remains unknown.
METHODS
SREBP's transcriptional activities were analyzed using an SRE-luciferase (SRE-luc) reporter in 293T cells, Huh7 hepatoma cells, and primary human hepatocytes following a variety of conditions, including ectopic expression of HSD17B6, HSD17B6 mutants defective in its enzymatic activities, knockdown of HSD17B6, and cholesterol starvation. The interaction between HSD17B6 and SREBP/SCAP/INSIG complex was analyzed in 293T cells, Huh7 cells and mouse liver upon ectopic expression of HSD17B6 and its mutants; the interaction was also analyzed using endogenous proteins. The impacts of HSD17B6 on SREBP target expression, glucose tolerance, diet-induced obesity, and type 2 diabetes (T2D) were examined using Huh7 cells in vitro, and with C57BL/6 and NONcNZO10/LtJ T2D mice in vivo.
RESULTS
HSD17B6 binds to the SREBP/SCAP/INSIG complex and inhibits SREBP signaling in cultured hepatocytes and mouse liver. Although HSD17B6 plays a role in maintaining the equilibrium of 5α-dihydrotestosterone (DHT) in the prostate, a mutant defective in androgen metabolism was as effective as HSD17B6 in inhibiting SREBP signaling. Hepatic expression of both HSD17B6 and the defective mutant improved glucose intolerance and reduced hepatic triglyceride content in diet-induced obese C57BL/6 mice, while hepatic knockdown of HSD17B6 exacerbated glucose intolerance. Consistent with these results, liver-specific expression of HSD17B6 in a polygenic NONcNZO10/LtJ T2D mice reduced T2D development.
CONCLUSIONS
Our study unveils a novel role of HSD17B6 in inhibiting SREBP maturation via binding to the SREBP/SCAP/INSIG complex; this activity is independent of HSD17B6's sterol oxidase activity. Through this action, HSD17B6 improves glucose tolerance and attenuates the development of obesity-induced T2D. These findings position HSD17B6 as a potential therapeutic target for T2D therapy.
Topics: Male; Mice; Humans; Animals; Sterol Regulatory Element Binding Protein 1; Diabetes Mellitus, Type 2; Glucose Intolerance; Intracellular Signaling Peptides and Proteins; Mice, Inbred C57BL; Obesity; Glucose; Racemases and Epimerases
PubMed: 37330135
DOI: 10.1016/j.metabol.2023.155631 -
MedRxiv : the Preprint Server For... Jun 2023Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse...
Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.
PubMed: 37333246
DOI: 10.1101/2023.05.25.23290535 -
Physiology & Behavior Nov 2023Modern food environments are conducive to overeating and weight gain, but not everyone develops obesity. One reason for this may be that individuals differ in appetitive... (Review)
Review
Modern food environments are conducive to overeating and weight gain, but not everyone develops obesity. One reason for this may be that individuals differ in appetitive characteristics, or traits, that manifest early in life and go on to influence their behavioral susceptibility to gain and maintain excess weight. Classic studies showing that eating behavior in children can be measured by behavioral paradigms such as tests of caloric compensation and eating in the absence of hunger inspired the development and validation of psychometric instruments to assess appetitive characteristics in children and infants. A large body of evidence now suggests that food approach traits increase obesity risk, while food avoidant traits, such as satiety responsiveness, decrease obesity risk. Twin studies and genetic association studies have demonstrated that appetitive characteristics are heritable, consistent with a biological etiology. However, family environment factors are also influential, with mounting evidence suggesting that genetic and environmental risk factors interact and correlate with consequences for child eating behavior and weight. Further, neuroimaging studies are revealing that individual differences in responses to visual food cues, as well as to small tastes and larger amounts of food, across a number of brain regions involved in reward/motivation, cognitive control and other functions, may contribute to individual variation in appetitive behavior. Growing evidence also suggests that variation on psychometric measures of appetite is associated with regional differences in brain structure, and differential patterns of resting state functional connectivity. Large prospective studies beginning in infancy promise to enrich our understanding of neural and other biological underpinnings of appetite and obesity development in early life, and how the interplay between genetic and environmental factors affects appetitive systems. The biobehavioral susceptibility model of obesity development and maintenance outlined in this narrative review has implications for prevention and treatment of obesity in childhood.
Topics: Child; Infant; Humans; Appetite; Pediatric Obesity; Prospective Studies; Feeding Behavior; Weight Gain; Neuroimaging; Body Mass Index
PubMed: 37544571
DOI: 10.1016/j.physbeh.2023.114313 -
Biomedicines Jan 2023Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease's susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients.
PubMed: 36830856
DOI: 10.3390/biomedicines11020319 -
JAMA Cardiology Jul 2022Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM...
IMPORTANCE
Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death in young people. Although rare genetic variants are well-established contributors to HCM risk, common genetic variants have recently been implicated in disease pathogenesis.
OBJECTIVE
To assess the contributions of rare and common genetic variation to risk of HCM in the general population.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study of the UK Biobank (data from 2006-2010) and the Mass General Brigham Biobank (2010-2019) assessed the relative and joint contributions of rare genetic variants and a common variant (polygenic) score to risk of HCM. Both rare and common variant predictors were then evaluated in the context of relevant clinical risk factors. Data analysis was conducted from May 2021 to February 2022.
EXPOSURES
Pathogenic rare variants, common-variant (polygenic) score, and clinical risk factors.
MAIN OUTCOMES AND MEASURES
Risk of HCM.
RESULTS
The primary study population comprised 184 511 individuals from the UK Biobank. Mean (SD) age was 56 (8) years, 83 690 (45%) of participants were men, and 204 (0.1%) participants had HCM. Of 51 genes included in clinical genetic testing panels for HCM, pathogenic or likely pathogenic variants in 14 core genes (designated by the American College of Medical Genetics and Genomics [ACMG]) were associated with 55-fold higher odds (95% CI, 35-83) of HCM, while those in the remaining 37 non-ACMG genes were not significantly associated with HCM (OR, 1.8; 95% CI, 0.6-4.0). ClinVar pathogenic or likely pathogenic mutations in MYBPC3 (OR, 72; 95% CI, 39-124) and MYH7 (OR, 61; 95% CI, 26-121) were strongly associated with HCM, as were loss-of-function variants in ALPK3 (OR, 13; 95% CI, 4.4-28). A polygenic score was strongly associated with HCM (OR per SD increase in score, 1.6; 95% CI, 1.4-1.8), with concordant results in the Mass General Brigham Biobank. Genetic factors enhanced clinical risk prediction for HCM: addition of rare variant carrier status and the polygenic score to clinical risk factors (obesity, hypertension, atrial fibrillation, and coronary artery disease) improved the area under the receiver operator characteristic curve from 0.71 (95% CI, 0.65-0.77) to 0.82 (95% CI, 0.77-0.87).
CONCLUSIONS AND RELEVANCE
Both rare and common genetic variants contribute substantially to HCM susceptibility in the general population and improve HCM risk prediction beyond that achieved with clinical factors.
Topics: Adolescent; Biological Specimen Banks; Cardiomyopathy, Hypertrophic; Cohort Studies; Death, Sudden, Cardiac; Female; Humans; Male; Middle Aged; Mutation
PubMed: 35583889
DOI: 10.1001/jamacardio.2022.1061