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Current Genomics Jul 2022Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex... (Review)
Review
Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient's family is also of importance. The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.
PubMed: 36777005
DOI: 10.2174/1389202923666220426093436 -
Nature Human Behaviour May 2021Eating behaviours may be expressions of genetic risk for obesity and are potential antecedents of later eating disorders. However, childhood eating behaviours are...
Eating behaviours may be expressions of genetic risk for obesity and are potential antecedents of later eating disorders. However, childhood eating behaviours are heterogeneous and transient. Here we show associations between polygenic scores for body mass index (BMI-PGS) and anorexia nervosa (AN-PGS) with eating behaviour trajectories during the first 10 years of life using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), n = 7,825. Results indicated that 1 s.d. increase in the BMI-PGS was associated with a 30-37% increased risk for early- and mid-childhood overeating. In contrast, 1 s.d. increase in BMI-PGS was associated with a 20% decrease in risk of persistent high levels of undereating and a 15% decrease in risk of persistent fussy eating. There was no evidence for a significant association between AN-PGS and eating behaviour trajectories. Our results support the notion that child eating behaviours share common genetic variants associated with BMI.
Topics: Anorexia Nervosa; Body Mass Index; Body Weight; Child; Feeding Behavior; Genetic Predisposition to Disease; Genomics; Humans; Multifactorial Inheritance
PubMed: 33432183
DOI: 10.1038/s41562-020-01019-y -
Reviews in Endocrine & Metabolic... Oct 2023Obesity is a common complex trait that elevates the risk for various diseases, including type 2 diabetes and cardiovascular disease. A combination of environmental and... (Review)
Review
Obesity is a common complex trait that elevates the risk for various diseases, including type 2 diabetes and cardiovascular disease. A combination of environmental and genetic factors influences the pathogenesis of obesity. Advances in genomic technologies have driven the identification of multiple genetic loci associated with this disease, ranging from studying severe onset cases to investigating common multifactorial polygenic forms. Additionally, findings from epigenetic analyses of modifications to the genome that do not involve changes to the underlying DNA sequence have emerged as key signatures in the development of obesity. Such modifications can mediate the effects of environmental factors, including diet and lifestyle, on gene expression and clinical presentation. This review outlines what is known about the genetic and epigenetic contributors to obesity susceptibility, along with the albeit limited therapeutic options currently available. Furthermore, we delineate the potential mechanisms of actions through which epigenetic changes can mediate environmental influences and the related opportunities they present for future interventions in the management of obesity.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity; Epigenesis, Genetic; Epigenomics; Genome-Wide Association Study
PubMed: 37032403
DOI: 10.1007/s11154-023-09804-6 -
Current Opinion in Clinical Nutrition... Jul 2022Intrahepatic triglyceride (IHTG) content is determined by substrate flux to, fatty acid synthesis and partitioning within, and triglyceride disposal from the liver.... (Review)
Review
PURPOSE OF REVIEW
Intrahepatic triglyceride (IHTG) content is determined by substrate flux to, fatty acid synthesis and partitioning within, and triglyceride disposal from the liver. Dysregulation of these processes may cause IHTG accumulation, potentially leading to nonalcoholic fatty liver disease. The aetiology of IHTG accumulation has not been fully elucidated; however, environmental factors and heritability are important. Here, we review recent evidence regarding the contribution of metabolic and genetic components of IHTG accumulation.
RECENT FINDINGS
Obesity and insulin resistance are the primary metabolic drivers for IHTG accumulation. These risk factors have pronounced and seemingly overlapping effects on all processes involved in determining IHTG content. The strong and interchangeable associations between obesity, insulin resistance and IHTG make it challenging to determine their relative contributions. Genome-wide association studies have identified a growing list of single nucleotide polymorphisms associated with IHTG content and recent work has begun to elucidate their mechanistic effects. The mechanisms underlying metabolic and genetic drivers of IHTG appear to be distinct.
SUMMARY
Both metabolic and genetic factors influence IHTG content by apparently distinct mechanisms. Further work is needed to determine metabolic and genetic interaction effects, which may lead to more personalized and potentially efficacious therapeutic interventions. The development of a comprehensive polygenic risk score for IHTG content may help facilitate this.
Topics: Genome-Wide Association Study; Glucose Clamp Technique; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity; Triglycerides
PubMed: 35762159
DOI: 10.1097/MCO.0000000000000838 -
Clinical Gastroenterology and... Mar 2022A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content...
BACKGROUND & AIMS
A polygenic risk score based on well-known genetic variants in PNPLA3, TM6SF2, MBOAT7, and GCKR predicts hepatic fat content (polygenic risk score-hepatic fat content [PRS-HFC]). Here, we hypothesized that the addition of PRS-HFC to clinical fibrosis scores may improve risk stratification and prediction of severe liver disease (SLD).
METHODS
We used data from 266,687 individuals in the UK Biobank, evaluating the incidence of cirrhosis, decompensated liver disease, hepatocellular carcinoma, and/or liver transplantation during a median follow-up period of 9 years. Nonalcoholic fatty liver disease fibrosis score, Fibrosis-4, aspartate aminotransferase-to-platelet ratio, BARD, and Forns scores, and PRS-HFC, were computed. All analyses were stratified according to the presence of diabetes, obesity, and a positive fatty liver index (≥60).
RESULTS
Unfavorable genetics (PRS-HFC, ≥0.396) further stratified the risk of SLD in subjects in intermediate-/high-risk classes of fibrosis scores, with a higher effect in those with metabolic risk factors, and the prediction was improved by integrating PRS-HFC (areas under the receiver operating characteristic increased for all scores with a P value of approximately 10 to 10, except for the aspartate aminotransferase-to-platelet ratio in the overall population and in subjects with obesity). PRS-HFC improved diagnostic accuracies and positive predictive values for SLD in intermediate-high clinical score risk classes. Risk stratification and prediction were not affected or were poorly affected by unfavorable genetics in subjects without metabolic risk factors.
CONCLUSIONS
Integration of genetics with clinical fibrosis scores refines individual risk and prediction for SLD, mainly in individuals at risk for nonalcoholic fatty liver disease. These data provide evidence from a prospective cohort that common genetic variants capture additional prognostic insights not conveyed by validated clinical/biochemical parameters.
Topics: Fibrosis; Humans; Liver; Liver Cirrhosis; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Prospective Studies; Risk Assessment; Risk Factors
PubMed: 34091049
DOI: 10.1016/j.cgh.2021.05.056 -
International Journal of Obesity (2005) Jun 2021Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have...
BACKGROUND
Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents.
METHODS
The analyses are based on 8609 repeated observations from 3098 participants aged 2-16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification.
RESULTS
The PRS was associated with BMI (beta estimate [95% confidence interval (95%-CI)] = 0.33 [0.30, 0.37], r = 0.11, p value = 7.9 × 10) and WC (beta [95%-CI] = 0.36 [0.32, 0.40], r = 0.09, p value = 1.8 × 10). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta [95%-CI] = 0.40 [0.34, 0.45]) in comparison to children from central Europe (beta [95%-CI] = 0.29 [0.23, 0.34]), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta [95%-CI] = 0.48 [0.38, 0.59]) in comparison to children of parents with a high level of education (beta [95%-CI] = 0.30 [0.26, 0.34]), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta [95%-CI] interaction = -0.02 [-0.04,-0.01]) and shorter screen times (beta [95%-CI] interaction = 0.02 [0.00, 0.03]).
CONCLUSIONS
Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Europe; Female; Genome-Wide Association Study; Humans; Life Style; Male; Pediatric Obesity; Social Factors
PubMed: 33753884
DOI: 10.1038/s41366-021-00795-5 -
JAMA Network Open Mar 2024Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic...
IMPORTANCE
Despite consistent public health recommendations, obesity rates in the US continue to increase. Physical activity recommendations do not account for individual genetic variability, increasing risk of obesity.
OBJECTIVE
To use activity, clinical, and genetic data from the All of Us Research Program (AoURP) to explore the association of genetic risk of higher body mass index (BMI) with the level of physical activity needed to reduce incident obesity.
DESIGN, SETTING, AND PARTICIPANTS
In this US population-based retrospective cohort study, participants were enrolled in the AoURP between May 1, 2018, and July 1, 2022. Enrollees in the AoURP who were of European ancestry, owned a personal activity tracking device, and did not have obesity up to 6 months into activity tracking were included in the analysis.
EXPOSURE
Physical activity expressed as daily step counts and a polygenic risk score (PRS) for BMI, calculated as weight in kilograms divided by height in meters squared.
MAIN OUTCOME AND MEASURES
Incident obesity (BMI ≥30).
RESULTS
A total of 3124 participants met inclusion criteria. Among 3051 participants with available data, 2216 (73%) were women, and the median age was 52.7 (IQR, 36.4-62.8) years. The total cohort of 3124 participants walked a median of 8326 (IQR, 6499-10 389) steps/d over a median of 5.4 (IQR, 3.4-7.0) years of personal activity tracking. The incidence of obesity over the study period increased from 13% (101 of 781) to 43% (335 of 781) in the lowest and highest PRS quartiles, respectively (P = 1.0 × 10-20). The BMI PRS demonstrated an 81% increase in obesity risk (P = 3.57 × 10-20) while mean step count demonstrated a 43% reduction (P = 5.30 × 10-12) when comparing the 75th and 25th percentiles, respectively. Individuals with a PRS in the 75th percentile would need to walk a mean of 2280 (95% CI, 1680-3310) more steps per day (11 020 total) than those at the 50th percentile to have a comparable risk of obesity. To have a comparable risk of obesity to individuals at the 25th percentile of PRS, those at the 75th percentile with a baseline BMI of 22 would need to walk an additional 3460 steps/d; with a baseline BMI of 24, an additional 4430 steps/d; with a baseline BMI of 26, an additional 5380 steps/d; and with a baseline BMI of 28, an additional 6350 steps/d.
CONCLUSIONS AND RELEVANCE
In this cohort study, the association between daily step count and obesity risk across genetic background and baseline BMI were quantified. Population-based recommendations may underestimate physical activity needed to prevent obesity among those at high genetic risk.
Topics: Female; Humans; Middle Aged; Male; Cohort Studies; Retrospective Studies; Population Health; Obesity; Exercise; Genetic Risk Score
PubMed: 38536175
DOI: 10.1001/jamanetworkopen.2024.3821 -
Abdominal obesity is a more important causal risk factor for pancreatic cancer than overall obesity.European Journal of Human Genetics :... Aug 2023Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct...
Obesity and type 2 diabetes (T2D) are associated with increased risk of pancreatic cancer. Here we assessed the relationship between pancreatic cancer and two distinct measures of obesity, namely total adiposity, using BMI, versus abdominal adiposity, using BMI adjusted waist-to-hip ratio (WHRadjBMI) by utilising polygenic scores (PGS) and Mendelian randomisation (MR) analyses. We constructed z-score weighted PGS for BMI and WHRadjBMI using publicly available data and tested for their association with pancreatic cancer defined in UK biobank (UKBB). Using publicly available summary statistics, we then performed bi-directional MR analyses between the two obesity traits and pancreatic cancer. PGS was significantly (multiple testing-corrected) associated with pancreatic cancer (OR[95%CI] = 1.0804[1.025-1.14], P = 0.0037). The significance of association declined after T2D adjustment (OR[95%CI] = 1.073[1.018-1.13], P = 0.00904). PGS association with pancreatic cancer was at the margin of statistical significance (OR[95%CI] = 1.047[0.99-1.104], P = 0.086). T2D adjustment effectively lost any suggestive association of PGS with pancreatic cancer (OR[95%CI] = 1.039[0.99-1.097], P = 0.14). MR analyses showed a nominally significant causal effect of WHRadjBMI on pancreatic cancer (OR[95%CI] = 1.00095[1.00011-1.0018], P = 0.027) but not for BMI on pancreatic cancer. Overall, we show that abdominal adiposity measured using WHRadjBMI, may be a more important causal risk factor for pancreatic cancer compared to total adiposity, with T2D being a potential driver of this relationship.
Topics: Humans; Diabetes Mellitus, Type 2; Obesity, Abdominal; Body Mass Index; Obesity; Risk Factors; Adiposity; Pancreatic Neoplasms; Genome-Wide Association Study
PubMed: 37161092
DOI: 10.1038/s41431-023-01301-3 -
Annals of Human Biology Feb 2023Like other complex phenotypes, human height reflects a combination of environmental and genetic factors, but is notable for being exceptionally easy to measure. Height... (Review)
Review
CONTEXT
Like other complex phenotypes, human height reflects a combination of environmental and genetic factors, but is notable for being exceptionally easy to measure. Height has therefore been commonly used to make observations later generalised to other phenotypes though the appropriateness of such generalisations is not always considered.
OBJECTIVES
We aimed to assess height's suitability as a model for other complex phenotypes and review recent advances in height genetics with regard to their implications for complex phenotypes more broadly.
METHODS
We conducted a comprehensive literature search in PubMed and Google Scholar for articles relevant to the genetics of height and its comparatibility to other phenotypes.
RESULTS
Height is broadly similar to other phenotypes apart from its high heritability and ease of measurment. Recent genome-wide association studies (GWAS) have identified over 12,000 independent signals associated with height and saturated height's common single nucleotide polymorphism based heritability of height within a subset of the genome in individuals similar to European reference populations.
CONCLUSIONS
Given the similarity of height to other complex traits, the saturation of GWAS's ability to discover additional height-associated variants signals potential limitations to the omnigenic model of complex-phenotype inheritance, indicating the likely future power of polygenic scores and risk scores, and highlights the increasing need for large-scale variant-to-gene mapping efforts.
Topics: Humans; Multifactorial Inheritance; Genome-Wide Association Study; Phenotype; Genome, Human; Polymorphism, Single Nucleotide
PubMed: 37343163
DOI: 10.1080/03014460.2023.2215546 -
EBioMedicine Oct 2022Obstructive Sleep Apnoea (OSA) often co-occurs with cardiometabolic and pulmonary diseases. This study is to apply genetic analysis methods to explain the associations...
BACKGROUND
Obstructive Sleep Apnoea (OSA) often co-occurs with cardiometabolic and pulmonary diseases. This study is to apply genetic analysis methods to explain the associations between OSA and related phenotypes.
METHODS
In the Hispanic Community Healthy Study/Study of Latinos, we estimated genetic correlations ρ between the respiratory event index (REI) and 54 anthropometric, glycemic, cardiometabolic, and pulmonary phenotypes. We used summary statistics from published genome-wide association studies to construct Polygenic Risk Scores (PRSs) representing the genetic basis of each correlated phenotype (ρ>0.2 and p-value<0.05), and of OSA. We studied the association of the PRSs of the correlated phenotypes with both REI and OSA (REI≥5), and the association of OSA PRS with the correlated phenotypes. Causal relationships were tested using Mendelian Randomization (MR) analysis.
FINDINGS
The dataset included 11,155 participants, 31.03% with OSA. 22 phenotypes were genetically correlated with REI. 10 PRSs covering obesity and fat distribution (BMI, WHR, WHRadjBMI), blood pressure (DBP, PP, MAP), glycaemic control (fasting insulin, HbA1c, HOMA-B) and insomnia were associated with REI and/or OSA. OSA PRS was associated with BMI, WHR, DBP and glycaemic traits (fasting insulin, HbA1c, HOMA-B and HOMA-IR). MR analysis identified robust causal effects of BMI and WHR on OSA, and probable causal effects of DBP, PP, and HbA1c on OSA/REI.
INTERPRETATION
There are shared genetic underpinnings of anthropometric, blood pressure, and glycaemic phenotypes with OSA, with evidence for causal relationships between some phenotypes.
FUNDING
Described in Acknowledgments.
Topics: Blood Glucose; Body Mass Index; Cardiovascular Diseases; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Insulin; Phenotype; Sleep Apnea, Obstructive
PubMed: 36174398
DOI: 10.1016/j.ebiom.2022.104288