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BMC Genomics Jun 2024Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a...
Genome-wide association study identifies novel susceptible loci and evaluation of polygenic risk score for chronic obstructive pulmonary disease in a Taiwanese population.
BACKGROUND
Chronic Obstructive Pulmonary Disease (COPD) describes a group of progressive lung diseases causing breathing difficulties. While COPD development typically involves a complex interplay between genetic and environmental factors, genetics play a role in disease susceptibility. This study used genome-wide association studies (GWAS) and polygenic risk score (PRS) to elucidate the genetic basis for COPD in Taiwanese patients.
RESULTS
GWAS was performed on a Taiwanese COPD case-control cohort with a sample size of 5,442 cases and 17,681 controls. Additionally, the PRS was calculated and assessed in our target groups. GWAS results indicate that although there were no single nucleotide polymorphisms (SNPs) of genome-wide significance, prominent COPD susceptibility loci on or nearby genes such as WWTR1, EXT1, INTU, MAP3K7CL, MAMDC2, BZW1/CLK1, LINC01197, LINC01894, and CFAP95 (C9orf135) were identified, which had not been reported in previous studies. Thirteen susceptibility loci, such as CHRNA4, AFAP1, and DTWD1, previously reported in other populations were replicated and confirmed to be associated with COPD in Taiwanese populations. The PRS was determined in the target groups using the summary statistics from our base group, yielding an effective association with COPD (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.17, p = 0.011). Furthermore, replication a previous lung function trait PRS model in our target group, showed a significant association of COPD susceptibility with PRS of Forced Expiratory Volume in one second (FEV)/Forced Vital Capacity (FCV) (OR 0.89, 95% CI 0.83-0.95, p = 0.001).
CONCLUSIONS
Novel COPD-related genes were identified in the studied Taiwanese population. The PRS model, based on COPD or lung function traits, enables disease risk estimation and enhances prediction before suffering. These results offer new perspectives on the genetics of COPD and serve as a basis for future research.
Topics: Pulmonary Disease, Chronic Obstructive; Humans; Genome-Wide Association Study; Taiwan; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Male; Female; Aged; Multifactorial Inheritance; Case-Control Studies; Middle Aged; Risk Factors; Genetic Loci; Asian People; Genetic Risk Score
PubMed: 38886662
DOI: 10.1186/s12864-024-10526-5 -
PloS One 2024Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions....
Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.
Topics: Humans; Male; Female; Long QT Syndrome; Middle Aged; Electrocardiography; Multifactorial Inheritance; Risk Factors; Aged; Adult; Torsades de Pointes; Case-Control Studies; Phenethylamines; Genetic Risk Score; Sulfonamides
PubMed: 38885227
DOI: 10.1371/journal.pone.0303261 -
Molecular Autism Jun 2024Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in...
BACKGROUND
Positive assortative mating (AM) in several neuropsychiatric traits, including autism, has been noted. However, it is unknown whether the pattern of AM is different in phenotypically defined autism subgroups [e.g., autism with and without intellectually disability (ID)]. It is also unclear what proportion of the phenotypic AM can be explained by the genetic similarity between parents of children with an autism diagnosis, and the consequences of AM on the genetic structure of the population.
METHODS
To address these questions, we analyzed two family-based autism collections: the Simons Foundation Powering Autism Research for Knowledge (SPARK) (1575 families) and the Simons Simplex Collection (SSC) (2283 families).
RESULTS
We found a similar degree of phenotypic and ancestry-related AM in parents of children with an autism diagnosis regardless of the presence of ID. We did not find evidence of AM for autism based on autism polygenic scores (PGS) (at a threshold of |r|> 0.1). The adjustment of ancestry-related AM or autism PGS accounted for only 0.3-4% of the fractional change in the estimate of the phenotypic AM. The ancestry-related AM introduced higher long-range linkage disequilibrium (LD) between single nucleotide polymorphisms (SNPs) on different chromosomes that are highly ancestry-informative compared to SNPs that are less ancestry-informative (D on the order of 1 × 10).
LIMITATIONS
We only analyzed participants of European ancestry, limiting the generalizability of our results to individuals of non-European ancestry. SPARK and SSC were both multicenter studies. Therefore, there could be ancestry-related AM in SPARK and SSC due to geographic stratification. The study participants from each site were unknown, so we were unable to evaluate for geographic stratification.
CONCLUSIONS
This study showed similar patterns of AM in autism with and without ID, and demonstrated that the common genetic influences of autism are likely relevant to both autism groups. The adjustment of ancestry-related AM and autism PGS accounted for < 5% of the fractional change in the estimate of the phenotypic AM. Future studies are needed to evaluate if the small increase of long-range LD induced by ancestry-related AM has impact on the downstream analysis.
Topics: Humans; Autistic Disorder; Phenotype; Male; Female; Linkage Disequilibrium; Multifactorial Inheritance; Child; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Adult; Intellectual Disability
PubMed: 38877467
DOI: 10.1186/s13229-024-00605-5 -
Journal of the American Heart... Jun 2024
Topics: Humans; Female; Coronary Artery Disease; Sex Factors; Prognosis; Multifactorial Inheritance; Risk Assessment; Genetic Predisposition to Disease; Risk Factors; Male
PubMed: 38874071
DOI: 10.1161/JAHA.123.034946 -
Revue Medicale de Liege Jun 2024Despite screening programmes, numerous clinical studies and new breast imaging techniques, breast cancer incidence for women continues to rise. The arrival of predictive... (Review)
Review
Despite screening programmes, numerous clinical studies and new breast imaging techniques, breast cancer incidence for women continues to rise. The arrival of predictive and personalized medicine could clearly redefine our screening recommendations. One promising approach to improving screening would be to use tools to predict the risk of developing breast cancer, including polygenic risk scores (PRS). This approach will enable us to offer women risk-based screening by adapting the frequency, type and age of screening. This article reviews some definitions of the PRS and breast cancer screening. We also explain the risk assessment models that have been developed and the various studies underway on personalized screening.
Topics: Humans; Breast Neoplasms; Female; Early Detection of Cancer; Risk Assessment; Preventive Medicine; Multifactorial Inheritance; Genetic Predisposition to Disease; Genetic Risk Score
PubMed: 38869126
DOI: No ID Found -
Cureus Jun 2024Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic...
Metformin Monotherapy With and Without Lifestyle Changes Affects Anthropometric Parameters, Blood Pressure, Blood Glucose, and Lipid Profile in Indian Patients With Newly Diagnosed Type 2 Diabetes.
INTRODUCTION
Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic (polygenic inheritance), endogenous (obesity and or hormonal factors), and environmental factors (e.g., obesogenic environment, endocrine disrupting chemicals, stress, and medicines). The prevalence of T2DM has increased over the past few decades. South Asians, including Indians, are more prone to central adiposity and develop lifestyle diseases like T2DM at body mass index values lower than those considered normal for the Western population. Generally, the first line of treatment is metformin monotherapy with lifestyle changes in patients with T2DM. Most of the research conducted on this drug is on Western subjects. Since the Indian population has genetic differences in the site of deposition of adipose and is more prone to develop lifestyle diseases, the effect of metformin may be different in Indians.
METHODS
Seventy-one (34 female, non-pregnant, non-lactating) adults with newly diagnosed T2DM were recruited in this short-duration pilot study after obtaining written informed consent. Patients regularly taking any drug were excluded, as were patients with chronic comorbidities. Treatment was initiated with metformin 500 mg OD. Lifestyle changes were recommended according to the age and physical condition of the patients. Anthropometric parameters (age, weight, height, BMI, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)), blood pressure, glycemic status (fasting and 2 h PP glucose and HbA1c), and lipid profile of the subjects were recorded before initiating and six months after initiating metformin monotherapy with lifestyle changes.
RESULTS
Small but statistically significant improvements were observed in the WHR,WHtR, blood pressure, blood glucose, and glycated hemoglobin. Although improvement was also observed in weight and lipid profile, these changes were not statistically significant.
CONCLUSION
This study shows that metformin monotherapy with lifestyle changes is suitable for patients of Indian origin and results in improvement in the WHR, WHtR, blood pressure, plasma glucose, and glycated hemoglobin.
PubMed: 38868550
DOI: 10.7759/cureus.62131 -
Nature Communications Jun 2024Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To...
Polygenic scores (PGSs) offer the ability to predict genetic risk for complex diseases across the life course; a key benefit over short-term prediction models. To produce risk estimates relevant to clinical and public health decision-making, it is important to account for varying effects due to age and sex. Here, we develop a novel framework to estimate country-, age-, and sex-specific estimates of cumulative incidence stratified by PGS for 18 high-burden diseases. We integrate PGS associations from seven studies in four countries (N = 1,197,129) with disease incidences from the Global Burden of Disease. PGS has a significant sex-specific effect for asthma, hip osteoarthritis, gout, coronary heart disease and type 2 diabetes (T2D), with all but T2D exhibiting a larger effect in men. PGS has a larger effect in younger individuals for 13 diseases, with effects decreasing linearly with age. We show for breast cancer that, relative to individuals in the bottom 20% of polygenic risk, the top 5% attain an absolute risk for screening eligibility 16.3 years earlier. Our framework increases the generalizability of results from biobank studies and the accuracy of absolute risk estimates by appropriately accounting for age- and sex-specific PGS effects. Our results highlight the potential of PGS as a screening tool which may assist in the early prevention of common diseases.
Topics: Humans; Male; Female; Multifactorial Inheritance; Incidence; Middle Aged; Genetic Predisposition to Disease; Adult; Aged; Diabetes Mellitus, Type 2; Risk Factors; Risk Assessment; Global Burden of Disease; Sex Factors; Age Factors
PubMed: 38866767
DOI: 10.1038/s41467-024-48938-2 -
Psychiatry Research Aug 2024Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into...
Given that anxiety disorders (AD) are associated with reduced vagally-mediated heart rate variability (HRV), genetic variants related to HRV may provide insight into anxiety etiology. This study used polygenic risk scores (PRS) to explore the genetic overlap between AD and HRV, and investigated whether HRV-related polymorphisms influence anxiety risk. Resting vagally-mediated HRV was measured using a wearable device in 188 European individuals (AD=101, healthy controls=87). AD PRS was tested for association with resting HRV, and HRV PRS for association with AD. We also investigated 15 significant hits from an HRV genome-wide association study (GWAS) for association with resting HRV and AD and if this association is mediated through resting HRV. The AD PRS and HRV PRS showed nominally significant associations with resting HRV and anxiety disorders, respectively. HRV GWAS variants associated with resting HRV were rs12980262 (NDUFA11), rs2680344 (HCN4), rs4262 and rs180238 (GNG11), and rs10842383 (LINC00477). Mediation analyses revealed that NDUFA11 rs12980262 A-carriers and GNG11 rs180238 and rs4262 C-carriers had higher anxiety risk through lower HRV. This study supports an anxiety-HRV genetic relationship, with HRV-related genetic variants translating to AD. This study encourages exploration of HRV genetics to understand mechanisms and identify novel treatment targets for anxiety.
Topics: Humans; Male; Female; Adult; Anxiety Disorders; Heart Rate; Multifactorial Inheritance; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Middle Aged; Young Adult; Biomarkers; Genetic Predisposition to Disease
PubMed: 38850888
DOI: 10.1016/j.psychres.2024.115982 -
BMC Oral Health Jun 2024Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary...
BACKGROUND
Individuals born with cleft lip and/or palate who receive corrective surgery regularly have abnormal growth in the midface region such that they exhibit premaxillary hypoplasia. However, there are also genetic contributions to craniofacial morphology in the midface region, so although these individuals appear to have Class III skeletal discrepancy, their molar relationship may be Class I. Past genome-wide association studies (GWASs) on skeletal Class II and III malocclusion suggested that multiple genetic markers contribute to these phenotypes via a multifactorial inheritance model, but research has yet to examine the genetic markers associated with dental Class I malocclusion. Thus, our goal was to conduct a family based GWAS to identify genes across the genome that are associated with Class I malocclusion, as defined by molar relations, in humans with and without clefts.
METHODS
Our cohort consisted of 739 individuals from 47 Filipino families originally recruited in 2006 to investigate the genetic basis of orofacial clefts. All individuals supplied blood samples for DNA extraction and genotyping, and a 5,766 single nucleotide polymorphism (SNP) custom panel was used for the analyses. We performed a transmission disequilibrium test for participants with and without clefts to identify genetic contributors potentially involved with Class I malocclusion.
RESULTS
In the total cohort, 13 SNPs had associations that reached the genomic control threshold (p < 0.005), while five SNPs were associated with Class I in the cohort of participants without clefts, including four associations that were identified in the total cohort. The associations for the SNPs ABCA4 rs952499, SOX1-OT rs726455, and RORA rs877228 are of particular interest, as past research found associations between these genes and various craniofacial phenotypes, including cleft lip and/or palate.
CONCLUSIONS
These findings support the multifactorial inheritance model for dental Class I malocclusion and suggest a common genetic basis for different aspects of craniofacial development.
Topics: Humans; Cleft Lip; Cleft Palate; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Female; Male; Malocclusion, Angle Class I; Cohort Studies; Linkage Disequilibrium; Child; Genotype; Adolescent; Genetic Markers; Adult; Phenotype; Multifactorial Inheritance; Young Adult
PubMed: 38849772
DOI: 10.1186/s12903-024-04444-x -
Nature Communications Jun 2024Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods...
Coronary artery disease (CAD) is the leading cause of death among adults worldwide. Accurate risk stratification can support optimal lifetime prevention. Current methods lack the ability to incorporate new information throughout the life course or to combine innate genetic risk factors with acquired lifetime risk. We designed a general multistate model (MSGene) to estimate age-specific transitions across 10 cardiometabolic states, dependent on clinical covariates and a CAD polygenic risk score. This model is designed to handle longitudinal data over the lifetime to address this unmet need and support clinical decision-making. We analyze longitudinal data from 480,638 UK Biobank participants and compared predicted lifetime risk with the 30-year Framingham risk score. MSGene improves discrimination (C-index 0.71 vs 0.66), age of high-risk detection (C-index 0.73 vs 0.52), and overall prediction (RMSE 1.1% vs 10.9%), in held-out data. We also use MSGene to refine estimates of lifetime absolute risk reduction from statin initiation. Our findings underscore our multistate model's potential public health value for accurate lifetime CAD risk estimation using clinical factors and increasingly available genetics toward earlier more effective prevention.
Topics: Humans; Coronary Artery Disease; Male; Female; Middle Aged; Electronic Health Records; Aged; Risk Assessment; Risk Factors; Adult; Genetic Predisposition to Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; United Kingdom; Longitudinal Studies; Multifactorial Inheritance
PubMed: 38849421
DOI: 10.1038/s41467-024-49296-9