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ELife Jul 2023Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis... (Meta-Analysis)
Meta-Analysis
Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.
Topics: Animals; Mice; Osteogenesis; Genome-Wide Association Study; Diabetes Mellitus, Type 2; Spine; Ossification of Posterior Longitudinal Ligament
PubMed: 37461309
DOI: 10.7554/eLife.86514 -
Nutrients Jul 2023Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory disorder with persistent airflow limitation and tissue destruction. We aimed to...
Impact of Lung-Related Polygenic Risk Scores on Chronic Obstructive Pulmonary Disease Risk and Their Interaction with w-3 Fatty Acid Intake in Middle-Aged and Elderly Individuals.
Chronic obstructive pulmonary disease (COPD) is a complex, progressive respiratory disorder with persistent airflow limitation and tissue destruction. We aimed to explore the genetic impact of COPD and its interaction with nutrient intake in 8840 middle-aged and elderly individuals from the Ansan/Ansung cohorts. Participants were diagnosed with COPD if the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) was less than 0.7 using spirometry, and if they were previously diagnosed with COPD by a physician. Genome-wide association studies (GWAS) were performed to screen for genetic variants associated with COPD risk. Among them, we selected the genetic variants that exhibited interactions using the generalized multifactor dimensionality reduction (GMDR) method. The polygenic risk score (PRS) was computed by summing the number of risk alleles in the SNP-SNP interaction models that adhered to specific rules. Subsequently, participants were categorized into low-PRS, medium-PRS, and high-PRS groups. The participants with COPD exhibited significantly lower FEV1/FVC ratios (0.64) than those without COPD (0.82). It was positively associated with inflammation markers (serum C-reactive protein and white blood cell levels). A higher proportion of COPD participants were smokers and engaged in regular exercise. The 5-SNP model consisted of _rs1585258, _rs1997571, _rs719601, _rs10405598, and _rs889294, and showed a significant association with COPD risk ( < 0.001). Participants in the high-PRS group of this model had a 2.2-fold higher risk of COPD than those in the low-PRS group after adjusting for covariates. The PRS interacted with w-3 fatty acid intake and exercise, thus influencing the risk of COPD. There was an increase in COPD incidence among individuals with a higher PRS, particularly those with low consumption of w-3 fatty acid and engaged in high levels of exercise. In conclusion, adults with a high-PRS are susceptible to COPD risk, and w-3 fatty acid intake and exercise may impact the risk of developing COPD, potentially applying to formulate precision medicines to prevent COPD.
Topics: Adult; Aged; Middle Aged; Humans; Fatty Acids; Genome-Wide Association Study; Pulmonary Disease, Chronic Obstructive; Lung; Risk Factors; Forced Expiratory Volume; Vital Capacity; Spirometry; GTPase-Activating Proteins
PubMed: 37447386
DOI: 10.3390/nu15133062 -
Nature Genetics Aug 2023Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point...
Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.
Topics: Humans; Multifactorial Inheritance; Quantitative Trait Loci; Genome-Wide Association Study; Genetic Predisposition to Disease; Phenotype; Polymorphism, Single Nucleotide
PubMed: 37443254
DOI: 10.1038/s41588-023-01443-6 -
Diabetologia Sep 2023Iterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong... (Review)
Review
Iterative advances in understanding of the genetics of type 1 diabetes have identified >70 genetic regions associated with risk of the disease, including strong associations across the HLA class II region that account for >50% of heritability. The increased availability of genetic data combined with the decreased costs of generating these data, have facilitated the development of polygenic scores that aggregate risk variants from associated loci into a single number: either a genetic risk score (GRS) or a polygenic risk score (PRS). PRSs incorporate the risk of many possibly correlated variants from across the genome, even if they do not reach genome-wide significance, whereas GRSs estimate the cumulative contribution of a smaller subset of genetic variants that reach genome-wide significance. Type 1 diabetes GRSs have utility in diabetes classification, aiding discrimination between type 1 diabetes, type 2 diabetes and MODY. Type 1 diabetes GRSs are also being used in newborn screening studies to identify infants at risk of future presentation of the disease. Most early studies of type 1 diabetes genetics have been conducted in European ancestry populations, but, to develop accurate GRSs across diverse ancestries, large case-control cohorts from non-European populations are still needed. The current barriers to GRS implementation within healthcare are mainly related to a lack of guidance and knowledge on integration with other biomarkers and clinical variables. Once these limitations are addressed, there is huge potential for 'test and treat' approaches to be used to tailor care for individuals with type 1 diabetes.
Topics: Infant, Newborn; Humans; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Risk Factors; Biomarkers; Genome-Wide Association Study
PubMed: 37439792
DOI: 10.1007/s00125-023-05955-y -
BMC Medical Genomics Jul 2023We aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and...
BACKGROUND & AIMS
We aimed to assess the performance of European-derived polygenic risk scores (PRSs) for common metabolic diseases such as coronary artery disease (CAD), obesity, and type 2 diabetes (T2D) in the South Asian (SAS) individuals in the UK Biobank. Additionally, we studied the interaction between PRS and family history (FH) in the same population.
METHODS
To calculate the PRS, we used a previously published model derived from the EUR population and applied it to the individuals of SAS ancestry from the UKB study. Each PRS was adjusted according to an individual's genotype location in the principal components (PC) space to derive an ancestry adjusted PRS (aPRS). We calculated the percentiles based on aPRS and stratified individuals into three aPRS categories: low, intermediate, and high. Considering the intermediate-aPRS percentile as a reference, we compared the low and high aPRS categories and generated the odds ratio (OR) estimates. Further, we measured the combined role of aPRS and first-degree family history (FH) in the SAS population.
RESULTS
The risk of developing severe obesity for SAS individuals was almost twofold higher for individuals with high aPRS than for those with intermediate aPRS, with an OR of 1.95 (95% CI = 1.71-2.23, P < 0.01). At the same time, the risk of severe obesity was lower in the low-aPRS group (OR = 0.60, CI = 0.53-0.67, P < 0.01). Results in the same direction were found in the EUR data, where the low-PRS group had an OR of 0.53 (95% CI = 0.51-0.56, P < 0.01) and the high-PRS group had an OR of 2.06 (95% CI = 2.00-2.12, P < 0.01). We observed similar results for CAD and T2D. Further, we show that SAS individuals with a familial history of CAD and T2D with high-aPRS are associated with a higher risk of these diseases, implying a greater genetic predisposition.
CONCLUSION
Our findings suggest that CAD, obesity, and T2D GWAS summary statistics generated predominantly from the EUR population can be potentially used to derive aPRS in SAS individuals for risk stratification. With future GWAS recruiting more SAS participants and tailoring the PRSs towards SAS ancestry, the predictive power of PRS is likely to improve further.
Topics: Humans; Coronary Artery Disease; Diabetes Mellitus, Type 2; Obesity; Obesity, Morbid; Risk Factors; United Kingdom; Asian People; Multifactorial Inheritance
PubMed: 37438803
DOI: 10.1186/s12920-023-01598-5 -
BJGP Open Dec 2023Among children or adolescents with obesity, 40-70.5% will remain obese as adults according to their paediatric body mass index (BMI). The recommended management involves...
BACKGROUND
Among children or adolescents with obesity, 40-70.5% will remain obese as adults according to their paediatric body mass index (BMI). The recommended management involves changes in their nutritional habits (diet, physical activity, and sedentary lifestyle). Motivational interviewing (MI), a patient-centred consultation, has proven its worth in many fields where acting on behaviours is essential.
AIM
To investigate the use and outcomes of MI in the management of children and adolescents who are overweight and obese.
DESIGN & SETTING
A systematic review evaluated MI in the management of children and adolescents who are overweight and obese.
METHOD
PubMed, Web of Science, Cochrane Library, and CISMeF were searched between January 2022 and March 2022 for following terms: 'motivational interviewing', 'overweight or obesity', 'children or adolescent' to identify randomised controlled trials (RCTs). Inclusion criteria were interventions involving MI in children or adolescents who were commonly (polygenically) overweight or obese. Exclusion criteria were: studies before 1991; and articles not written in English or French. The first stage of the selection process was carried out by reading the titles and abstracts. A second stage was carried out by reading the complete studies. A secondary inclusion of articles was carried out following the reading of bibliographic references, mainly from systematic reviews and meta-analyses. The data were summarised in synthetic tables based on the Population, Intervention, Comparison, Outcomes, and Study (PICOS) tool.
RESULTS
From 444 articles the review identified 26 RCTs. Statistically significant results were found for all criteria (anthropometric and behavourial) in both children and adolescents. Quality of life and depression scores were also improved. Parental presence in the interview appeared to be essential for children, whereas for adolescents, the supportive involvement of parents outside of the interviews seemed more appropriate. The frequency and duration of the interventions played a major role in obtaining results, as did the number of people involved, and the diversity of the places where they are taken care of.
CONCLUSION
MI seems promising for children and adolescents with overweight or obesity, within the framework of a comprehensive, multiprofessional, family management, carried out over a long period with regular consultations.
PubMed: 37402547
DOI: 10.3399/BJGPO.2022.0145 -
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 -
Clinical and Experimental Pediatrics Dec 2023Recent advances in molecular genetics have advanced our understanding of the molecular mechanisms involved in pediatric endocrine disorders and now play a major role in...
Recent advances in molecular genetics have advanced our understanding of the molecular mechanisms involved in pediatric endocrine disorders and now play a major role in mainstream medical practice. The spectrum of endocrine genetic disorders has 2 extremes: Mendelian and polygenic. Mendelian or monogenic diseases are caused by rare variants of a single gene, each of which exerts a strong effect on disease risk. Polygenic diseases or common traits are caused by the combined effects of multiple genetic variants in conjunction with environmental and lifestyle factors. Testing for a single gene is preferable if the disease is phenotypically and/or geneically homogeneous. Next-generation sequencing (NGS) can be applied to phenotypically and genetically heterogeneous conditions. Genome-wide association studies (GWASs) have examined genetic variants across the entire genome in a large number of individuals who have been matched for population ancestry and assessed for a disease or trait of interest. Common endocrine diseases or traits, such as type 2 diabetes mellitus, obesity, height, and pubertal timing, result from the combined effects of multiple variants in various genes that are frequently found in the general population, each of which contributes a small individual effect. Isolated founder mutations can result from a true founder effect or an extreme reduction in population size. Studies of founder mutations offer powerful advantages for efficiently localizing the genes that underlie Mendelian disorders. The Korean population has settled in the Korean peninsula for thousands of years, and several recurrent mutations have been identified as founder mutations. The application of molecular technology has increased our understanding of endocrine diseases, which have impacted on the practice of pediatric endocrinology related to diagnosis and genetic counseling. This review focuses on the application of genomic research to pediatric endocrine diseases using GWASs and NGS technology for diagnosis and treatment.
PubMed: 37321569
DOI: 10.3345/cep.2022.00948 -
The Journal of Adolescent Health :... Sep 2023Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics...
PURPOSE
Overweight in youth is influenced by genes and environment. Gene-environment interaction (G×E) has been demonstrated in twin studies and recent developments in genetics allow for studying G×E using individual genetic predispositions for overweight. We examine genetic influence on trajectories of overweight during adolescence and early adulthood and determine whether genetic predisposition is attenuated by higher socioeconomic status and having physically active parents.
METHODS
Latent class growth models of overweight were fitted using data from the TRacking Adolescents' Individual Lives Survey (n = 2720). A polygenic score for body mass index (BMI) was derived using summary statistics from a genome-wide association study of adult BMI (N = ∼700,000) and tested as predictor of developmental pathways of overweight. Multinomial logistic regression models were used to examine effects of interactions of genetic predisposition with socioeconomic status and parental physical activity (n = 1675).
RESULTS
A three-class model of developmental pathways of overweight fitted the data best ("non-overweight", "adolescent-onset overweight", and "persistent overweight"). The polygenic score for BMI and socioeconomic status distinguished the persistent overweight and adolescent-onset overweight trajectories from the non-overweight trajectory. Only genetic predisposition differentiated the adolescent-onset from the persistent overweight trajectory. There was no evidence for G×E.
DISCUSSION
Higher genetic predisposition increased the risk of developing overweight during adolescence and young adulthood and was associated with an earlier age at onset. We did not find that genetic predisposition was offset by higher socioeconomic status or having physically active parents. Instead, lower socioeconomic status and higher genetic predisposition acted as additive risk factors for developing overweight.
Topics: Adult; Adolescent; Humans; Young Adult; Longitudinal Studies; Genetic Predisposition to Disease; Genome-Wide Association Study; Overweight; Body Mass Index; Pediatric Obesity; Risk Factors; Seizures
PubMed: 37318409
DOI: 10.1016/j.jadohealth.2023.04.028