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Frontiers in Public Health 2024Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV...
BACKGROUND
Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization.
METHODS
A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79.
RESULTS
Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women.
CONCLUSION
Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.
Topics: Humans; Cost-Benefit Analysis; China; Middle Aged; Male; Adult; Female; Nasopharyngeal Carcinoma; Aged; Markov Chains; Nasopharyngeal Neoplasms; Early Detection of Cancer; Mass Screening; Multifactorial Inheritance; Risk Factors; Risk Assessment
PubMed: 38756891
DOI: 10.3389/fpubh.2024.1375533 -
BMC Medical Genomics May 2024Polygenic risk scores (PRS) quantify an individual's genetic predisposition for different traits and are expected to play an increasingly important role in personalized...
BACKGROUND
Polygenic risk scores (PRS) quantify an individual's genetic predisposition for different traits and are expected to play an increasingly important role in personalized medicine. A crucial challenge in clinical practice is the generalizability and transferability of PRS models to populations with different ancestries. When assessing the generalizability of PRS models for continuous traits, the is a commonly used measure to evaluate prediction accuracy. While the is a well-defined goodness-of-fit measure for statistical linear models, there exist different definitions for its application on test data, which complicates interpretation and comparison of results.
METHODS
Based on large-scale genotype data from the UK Biobank, we compare three definitions of the on test data for evaluating the generalizability of PRS models to different populations. Polygenic models for several phenotypes, including height, BMI and lipoprotein A, are derived based on training data with European ancestry using state-of-the-art regression methods and are evaluated on various test populations with different ancestries.
RESULTS
Our analysis shows that the choice of the definition can lead to considerably different results on test data, making the comparison of values from the literature problematic. While the definition as the squared correlation between predicted and observed phenotypes solely addresses the discriminative performance and always yields values between 0 and 1, definitions of the based on the mean squared prediction error (MSPE) with reference to intercept-only models assess both discrimination and calibration. These MSPE-based definitions can yield negative values indicating miscalibrated predictions for out-of-target populations. We argue that the choice of the most appropriate definition depends on the aim of PRS analysis - whether it primarily serves for risk stratification or also for individual phenotype prediction. Moreover, both correlation-based and MSPE-based definitions of can provide valuable complementary information.
CONCLUSIONS
Awareness of the different definitions of the on test data is necessary to facilitate the reporting and interpretation of results on PRS generalizability. It is recommended to explicitly state which definition was used when reporting values on test data. Further research is warranted to develop and evaluate well-calibrated polygenic models for diverse populations.
Topics: Multifactorial Inheritance; Humans; Models, Genetic; Phenotype; Genetic Predisposition to Disease
PubMed: 38755654
DOI: 10.1186/s12920-024-01905-8 -
American Journal of Human Genetics Jun 2024Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of...
Obesity is a major risk factor for a myriad of diseases, affecting >600 million people worldwide. Genome-wide association studies (GWASs) have identified hundreds of genetic variants that influence body mass index (BMI), a commonly used metric to assess obesity risk. Most variants are non-coding and likely act through regulating genes nearby. Here, we apply multiple computational methods to prioritize the likely causal gene(s) within each of the 536 previously reported GWAS-identified BMI-associated loci. We performed summary-data-based Mendelian randomization (SMR), FINEMAP, DEPICT, MAGMA, transcriptome-wide association studies (TWASs), mutation significance cutoff (MSC), polygenic priority score (PoPS), and the nearest gene strategy. Results of each method were weighted based on their success in identifying genes known to be implicated in obesity, ranking all prioritized genes according to a confidence score (minimum: 0; max: 28). We identified 292 high-scoring genes (≥11) in 264 loci, including genes known to play a role in body weight regulation (e.g., DGKI, ANKRD26, MC4R, LEPR, BDNF, GIPR, AKT3, KAT8, MTOR) and genes related to comorbidities (e.g., FGFR1, ISL1, TFAP2B, PARK2, TCF7L2, GSK3B). For most of the high-scoring genes, however, we found limited or no evidence for a role in obesity, including the top-scoring gene BPTF. Many of the top-scoring genes seem to act through a neuronal regulation of body weight, whereas others affect peripheral pathways, including circadian rhythm, insulin secretion, and glucose and carbohydrate homeostasis. The characterization of these likely causal genes can increase our understanding of the underlying biology and offer avenues to develop therapeutics for weight loss.
Topics: Humans; Genome-Wide Association Study; Obesity; Body Mass Index; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Multifactorial Inheritance; Genetic Loci; Mendelian Randomization Analysis
PubMed: 38754426
DOI: 10.1016/j.ajhg.2024.04.016 -
Age and Ageing May 2024To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in...
OBJECTIVE
To investigate longitudinal associations between variations in the co-expression-based brain insulin receptor polygenic risk score and frailty, as well as change in frailty across follow-up.
METHODS
This longitudinal study included 1605 participants from the Helsinki Birth Cohort Study. Biologically informed expression-based polygenic risk scores for the insulin receptor gene network, which measure genetic variation in the function of the insulin receptor, were calculated for the hippocampal (hePRS-IR) and the mesocorticolimbic (mePRS-IR) regions. Frailty was assessed in at baseline in 2001-2004, 2011-2013 and 2017-2018 by applying a deficit accumulation-based frailty index. Analyses were carried out by applying linear mixed models and logistical regression models adjusted for adult socioeconomic status, birthweight, smoking and their interactions with age.
RESULTS
The FI levels of women were 1.19%-points (95% CI 0.12-2.26, P = 0.029) higher than in men. Both categorical and continuous hePRS-IR in women were associated with higher FI levels than in men at baseline (P < 0.05). In women with high hePRS-IR, the rate of change was steeper with increasing age compared to those with low or moderate hePRS-IR (P < 0.05). No associations were detected between mePRS-IR and frailty at baseline, nor between mePRS-IR and the increase in mean FI levels per year in either sex (P > 0.43).
CONCLUSIONS
Higher variation in the function of the insulin receptor gene network in the hippocampus is associated with increasing frailty in women. This could potentially offer novel targets for future drug development aimed at frailty and ageing.
Topics: Humans; Male; Female; Frailty; Receptor, Insulin; Aged; Longitudinal Studies; Middle Aged; Gene Regulatory Networks; Finland; Frail Elderly; Age Factors; Risk Factors; Aged, 80 and over; Aging; Sex Factors; Hippocampus; Multifactorial Inheritance; Geriatric Assessment; Brain; Antigens, CD
PubMed: 38752921
DOI: 10.1093/ageing/afae091 -
Developmental Cognitive Neuroscience Jun 2024Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few...
Impulsivity undergoes a normative developmental trajectory from childhood to adulthood and is thought to be driven by maturation of brain structure. However, few large-scale studies have assessed associations between impulsivity, brain structure, and genetic susceptibility in children. In 9112 children ages 9-10 from the ABCD study, we explored relationships among impulsivity (UPPS-P impulsive behavior scale; delay discounting), brain structure (cortical thickness (CT), cortical volume (CV), and cortical area (CA)), and polygenic scores for externalizing behavior (PGS). Both higher UPPS-P total scores and more severe delay-discounting had widespread, low-magnitude associations with smaller CA in frontal and temporal regions. No associations were seen between impulsivity and CV or CT. Additionally, higher PGS was associated with both higher UPPS-P scores and with smaller CA and CV in frontal and temporal regions, but in non-overlapping cortical regions, underscoring the complex interplay between genetics and brain structure in influencing impulsivity. These findings indicate that, within large-scale population data, CA is significantly yet weakly associated with each of these impulsivity measures and with polygenic risk for externalizing behaviors, but in distinct brain regions. Future work should longitudinally assess these associations through adolescence, and examine associated functional outcomes, such as future substance use and psychopathology.
Topics: Humans; Impulsive Behavior; Child; Male; Female; Self Report; Magnetic Resonance Imaging; Delay Discounting; Multifactorial Inheritance; Brain; Cerebral Cortex; Child Behavior
PubMed: 38749217
DOI: 10.1016/j.dcn.2024.101389 -
Human Brain Mapping May 2024The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical....
The high prevalence of conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) makes early prevention of AD extremely critical. Neuroticism, a heritable personality trait associated with mental health, has been considered a risk factor for conversion from aMCI to AD. However, whether the neuroticism genetic risk could predict the conversion of aMCI and its underlying neural mechanisms is unclear. Neuroticism polygenic risk score (N-PRS) was calculated in 278 aMCI patients with qualified genomic and neuroimaging data from ADNI. After 1-year follow-up, N-PRS in patients of aMCI-converted group was significantly greater than those in aMCI-stable group. Logistic and Cox survival regression revealed that N-PRS could significantly predict the early-stage conversion risk from aMCI to AD. These results were well replicated in an internal dataset and an independent external dataset of 933 aMCI patients from the UK Biobank. One sample Mendelian randomization analyses confirmed a potentially causal association from higher N-PRS to lower inferior parietal surface area to higher conversion risk of aMCI patients. These analyses indicated that neuroticism genetic risk may increase the conversion risk from aMCI to AD by impairing the inferior parietal structure.
Topics: Humans; Alzheimer Disease; Cognitive Dysfunction; Male; Female; Neuroticism; Aged; Magnetic Resonance Imaging; Multifactorial Inheritance; Disease Progression; Parietal Lobe; Aged, 80 and over; Mendelian Randomization Analysis; Middle Aged; Genetic Predisposition to Disease
PubMed: 38746977
DOI: 10.1002/hbm.26709 -
Psychiatry Research Jul 2024What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and...
What distinguishes vulnerability and resilience to posttraumatic stress disorder (PTSD) remains unclear. Levering traumatic experiences reporting, genetic data, and electronic health records (EHR), we investigated and predicted the clinical comorbidities (co-phenome) of PTSD vulnerability and resilience in the UK Biobank (UKB) and All of Us Research Program (AoU), respectively. In 60,354 trauma-exposed UKB participants, we defined PTSD vulnerability and resilience considering PTSD symptoms, trauma burden, and polygenic risk scores. EHR-based phenome-wide association studies (PheWAS) were conducted to dissect the co-phenomes of PTSD vulnerability and resilience. Significant diagnostic endpoints were applied as weights, yielding a phenotypic risk score (PheRS) to conduct PheWAS of PTSD vulnerability and resilience PheRS in up to 95,761 AoU participants. EHR-based PheWAS revealed three significant phenotypes positively associated with PTSD vulnerability (top association "Sleep disorders") and five outcomes inversely associated with PTSD resilience (top association "Irritable Bowel Syndrome"). In the AoU cohort, PheRS analysis showed a partial inverse relationship between vulnerability and resilience with distinct comorbid associations. While PheRS associations were linked to multiple phenotypes, PheRS showed inverse relationships with eye conditions. Our study unveils phenotypic differences in PTSD vulnerability and resilience, highlighting that these concepts are not simply the absence and presence of PTSD.
Topics: Humans; Stress Disorders, Post-Traumatic; Resilience, Psychological; Electronic Health Records; Female; Male; Middle Aged; Adult; Aged; Genetic Predisposition to Disease; Phenotype; Sleep Wake Disorders; Comorbidity; Multifactorial Inheritance; United Kingdom; Genome-Wide Association Study
PubMed: 38744179
DOI: 10.1016/j.psychres.2024.115950 -
JAMA Network Open May 2024Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height...
IMPORTANCE
Polygenic embryo screening (PES) is a novel technology that estimates the likelihood of developing future conditions (eg, diabetes or depression) and traits (eg, height or cognitive ability) in human embryos, with the goal of selecting which embryos to use. Given its commercial availability and concerns raised by researchers, clinicians, bioethicists, and professional organizations, it is essential to inform key stakeholders and relevant policymakers about the public's perspectives on this technology.
OBJECTIVE
To survey US adults to examine general attitudes, interests, and concerns regarding PES use.
DESIGN, SETTING, AND PARTICIPANTS
For this survey study, data were collected from 1 stratified sample and 1 nonprobability sample (samples 1 and 2, respectively) between March and July 2023. The surveys measured approval, interest, and concerns regarding various applications of PES. In the second sample, presentation of a list of potential concerns was randomized (presented at survey onset vs survey end). The survey was designed using Qualtrics and distributed to participants through Prolific, an online sampling firm. Sample 1 was nationally representative with respect to gender, age, and race and ethnicity; sample 2 was recruited without specific demographic criteria. Analyses were conducted between March 2023 and February 2024.
MAIN OUTCOMES AND MEASURES
Participants reported their approval, interest, and concerns regarding various applications of PES and outcomes screened (eg, traits and conditions). Statistical analysis was conducted using independent samples t tests and repeated-measures analyses of variance.
RESULTS
Of the 1435 respondents in sample 1, demographic data were available for 1427 (mean [SD] age, 45.8 [16.0] years; 724 women [50.7%]). Among these 1427 sample 1 respondents, 1027 (72.0%) expressed approval for PES and 1169 (81.9%) expressed some interest in using PES if already undergoing in vitro fertilization (IVF). Approval among these respondents for using PES for embryo selection was notably high for physical health conditions (1109 [77.7%]) and psychiatric health conditions (1028 [72.0%]). In contrast, there was minority approval for embryo selection based on PES for behavioral traits (514 [36.0%]) and physical traits (432 [30.3%]). Nevertheless, concerns about PES leading to false expectations and promoting eugenic practices were pronounced, with 787 of 1422 (55.3%) and 780 of 1423 (54.8%) respondents finding them very to extremely concerning, respectively. Sample 2 included 192 respondents (mean [SD] age 37.7 [12.2] years; 110 men [57.3%]). These respondents were presented concerns at survey onset (n = 95) vs survey end (n = 97), which was associated with less approval (28-percentage point decrease) and more uncertainty (24 percentage-point increase) but with only slightly higher disapproval (4 percentage-point increase).
CONCLUSIONS AND RELEVANCE
These findings suggest that it is critical for health care professionals and medical societies to consider and understand the perspectives of diverse stakeholders (eg, patients undergoing IVF, clinicians, and the general public), given the absence of regulation and the recent commercial availability of PES.
Topics: Humans; Female; Adult; Male; Public Opinion; Middle Aged; Surveys and Questionnaires; United States; Multifactorial Inheritance; Genetic Testing
PubMed: 38743425
DOI: 10.1001/jamanetworkopen.2024.10832 -
PloS One 2024The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene,...
The genetic complexity of polygenic traits represents a captivating and intricate facet of biological inheritance. Unlike Mendelian traits controlled by a single gene, polygenic traits are influenced by multiple genetic loci, each exerting a modest effect on the trait. This cumulative impact of numerous genes, interactions among them, environmental factors, and epigenetic modifications results in a multifaceted architecture of genetic contributions to complex traits. Given the well-characterized genome, diverse traits, and range of genetic resources, chicken (Gallus gallus) was employed as a model organism to dissect the intricate genetic makeup of a previously identified major Quantitative Trait Loci (QTL) for body weight on chromosome 1. A multigenerational advanced intercross line (AIL) of 3215 chickens whose genomes had been sequenced to an average of 0.4x was analyzed using genome-wide association study (GWAS) and variance-heterogeneity GWAS (vGWAS) to identify markers associated with 8-week body weight. Additionally, epistatic interactions were studied using the natural and orthogonal interaction (NOIA) model. Six genetic modules, two from GWAS and four from vGWAS, were strongly associated with the studied trait. We found evidence of both additive- and non-additive interactions between these modules and constructed a putative local epistasis network for the region. Our screens for functional alleles revealed a missense variant in the gene ribonuclease H2 subunit B (RNASEH2B), which has previously been associated with growth-related traits in chickens and Darwin's finches. In addition, one of the most strongly associated SNPs identified is located in a non-coding region upstream of the long non-coding RNA, ENSGALG00000053256, previously suggested as a candidate gene for regulating chicken body weight. By studying large numbers of individuals from a family material using approaches to capture both additive and non-additive effects, this study advances our understanding of genetic complexities in a highly polygenic trait and has practical implications for poultry breeding and agriculture.
Topics: Animals; Chickens; Quantitative Trait Loci; Genome-Wide Association Study; Body Weight; Polymorphism, Single Nucleotide; Epistasis, Genetic; Phenotype; Female; Multifactorial Inheritance; Male
PubMed: 38739572
DOI: 10.1371/journal.pone.0295109 -
International Journal of Molecular... Apr 2024Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying... (Review)
Review
Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.
Topics: Humans; Mitochondrial Diseases; Rare Diseases; Genetic Predisposition to Disease; Epigenesis, Genetic; Multifactorial Inheritance; Animals
PubMed: 38731822
DOI: 10.3390/ijms25094602