Transforming polygenic risk prediction: functional annotation and digital twin modeling with whole-exome sequencing

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Background Polygenic risk scores (PRSs) are widely used to assess genetic predisposition, but genotyping arrays typically target non-coding variants with limited functional annotation. In contrast, whole-exome sequencing (WES) maps protein-coding regions, providing insights that can enrich PRS interpretation and support novel computational frameworks infer individual predisposition. Results We evaluated WES for polygenic modeling using common exonic across 27 clinical biomarkers 17 disease outcomes in the UK Biobank (N = 105,506) applied approach VITO IAM Frontier cohort 30). achieved a 70.63% mapping rate of single-nucleotide polymorphisms (SNPs) genomic information, compared 11.64% arrays, most associations observed lipid, hepatic, renal biomarkers. performance was comparable derived from imputed array data linked 11 outcomes, including cardiovascular conditions. The best-performing develop digital twin model integrates biological pathways, gene tissue expression signatures, associations, validated by existing metabolomic data. Conclusions Our study demonstrates WES-derived PRSs effectively capture clinically relevant associations. However, through characterization associated variants, we show PRS, as model, could potentially explain individual-level variation provide information on how mediate risk.

Язык: Английский

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Advances in Forensic Neuropsychological Research

Опубликована: Янв. 1, 2025

Язык: Английский

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Navigating early risks: Differential outcomes in middle childhood and the compensatory role of kindergarten experiences

Journal of Child Psychology and Psychiatry, Год журнала: 2025, Номер unknown

Опубликована: Март 20, 2025

It has been proposed that early risk constellations link differentially to later developmental outcomes. However, existing studies often use a limited set of indicators, excluding genetic and child-based risks. is also unclear if the protective effects potential moderators, such as kindergarten experiences, differ across groups. Using data from Norwegian Mother, Father Child (MoBa) cohort study (n = 7,478), we established latent classes based on family, child, factors measured up 3 years age. The were then compared parent-rated internalizing externalizing symptoms academic performance at 8 years, well registry outcomes reflecting child diagnoses national test scores ages 11-14 years. Potential moderating (student-teacher closeness, social play behaviors structured pre-academic activities) examined. We identified five classes: "low risk" group (41.1%) performed best most behavioral A "resource (32.1%) struggled academically 11 while "family psychological (11.7%) showed mental health difficulties highest levels 12-14 "developmental (7.6%) exhibited more pronounced only, "preterm birth" (7.5%) moderate Close student-teacher relationships behaviors, but not activities, predicted improved small effect sizes whole sample, with evidence for differential responses Our groups linked outcomes, suggesting diverging pathways. investigated Kindergarten exerted groups, indicating they may universally benefit children independent their backgrounds.

Язык: Английский

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Efficient blockLASSO for polygenic scores with applications to all of us and UK Biobank

BMC Genomics, Год журнала: 2025, Номер 26(1)

Опубликована: Март 27, 2025

Abstract We develop a “block” LASSO (blockLASSO) approach for training polygenic scores (PGS) and demonstrate its use in All of Us (AoU) the UK Biobank (UKB). blockLASSO utilizes approximate block diagonal structure (due to chromosomal partition genome) linkage disequilibrium (LD). The new implementation can be used exploratory methods research where repeated PGS is necessary expensive. For 11 different phenotypes, two biobanks, across 5 ancestry groups (African, American, East Asian, European, South Asian) – we that generally as effective (global) LASSO. Previous work has shown penalized regression produce competitive alternative approaches. It been some phenotypes are more/less than others. Using sparse algorithms, an accurate trained type 1 diabetes (T1D) using $${\sim }100$$ ∼ 100 single nucleotide variants (SNVs), but body mass index (BMI) would need more 10k SNVs. produces similar while with just fraction per block. Within AoU (using only genetic information) T1D reaches AUC $$0.63_{\pm 0.02}$$ 0 . 63 ± 0.02 BMI correlation $$0.21_{\pm 0.01}$$ 21 0.01 , whereas global which finds $$0.65_{\pm 0.03}$$ 65 0.03 $$0.19_{\pm 19 . This computationally efficient scalable naive machine learning approaches makes it ideal investigations based on regression.

Язык: Английский

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Exploring Monogenic, Polygenic, and Epigenetic Models of Common Variable Immunodeficiency

Human Mutation, Год журнала: 2025, Номер 2025(1)

Опубликована: Янв. 1, 2025

Common variable immunodeficiency (CVID) is the most frequent symptomatic inborn error of immunity (IEI). CVID genetically heterogeneous and occurs in sporadic or familial forms with different inheritance patterns. Monogenic mutations have been found a low percentage patients, multifactorial polygenic may be involved unsolved patients. In complex disease model, epistatic effect multiple variants several genes environmental factors such as infections contribute. Epigenetic modifications, DNA methylation changes, are also proposed to pathogenesis. general, pathogenic mechanism molecular basis still unknown, identifying patterns association across genome models epigenetic modification profiles requires more studies. Here, we describe current knowledge genetic from monogenic, polygenic, aspects.

Язык: Английский

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Sexual Trauma, Polygenic Scores, and Mental Health Diagnoses and Outcomes

JAMA Psychiatry, Год журнала: 2024, Номер unknown

Опубликована: Окт. 30, 2024

Importance Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct screening efforts evaluate portability of polygenic scores across contexts. Objective To examine sexual trauma, liability health outcomes, diagnoses schizophrenia, bipolar disorder, major depressive disorder in a biobank setting. Design, Setting, Participants This association study was conducted using genotyping data from 96 002 participants hospital-linked located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high similarity 1000 Genomes Project [1KG] Northern European Utah reference population [1KG-EU-clustered] 11 047 1KG African-ancestry Yoruba Ibadan, Nigeria [1KG-YRI-clustered]), Mass General Brigham (MGB), Boston, Massachusetts (26 693 combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical analyzed included diagnostic billing codes notes spanning 1976 2023. Data analysis performed 2022 2024. Exposures Clinically documented trauma disclosures disorder. Main Outcomes Measures Diagnoses determined by aggregating related codes, were dependent variables logistic regression models including disclosure status, scores, their interactions as independent variables. Results Across VUMC MGB biobanks, analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 >89] years; 14 647 [54.9%] 58.0 1KG-YRI-clustered: 6961 [63.0%] 44.6 [10.1 years). Sexual history associated all conditions institutions (ORs ranged 8.83 [95% CI, 5.50-14.18] schizophrenia 1KG-YRI-clustered cohort 17.65 12.77-24.40] 1KG-EU-clustered cohort). jointly explained 3.8% 8.8% phenotypic variance. Schizophrenia had greater outcomes no (schizophrenia interaction: OR, 0.70 0.56-0.88]; 0.83 0.74-0.94]). Conclusions Relevance while correlated one another, joint severe large, diverse hospital population. Furthermore, respective those without disclosures, suggesting that predisposition measured be less impactful presence this factor.

Язык: Английский

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ADVANTAGES OF USING TRANSLATION, PARAPHRASING, AND PODCASTS TO IMPROVE NATURAL WRITING SKILLS

IJIET (International Journal of Indonesian Education and Teaching), Год журнала: 2024, Номер 8(2), С. 223 - 247

Опубликована: Июль 9, 2024

Most EFL students find it difficult to articulate themselves clearly in written assignments. To overcome those flaws, twenty-five college enrolled the program. The WhatsApp program was employed as a classroom tool because of online learning. teacher modified audio materials an attempt strengthen pupils' inadequate writing abilities. observed native speakers' use grammar their transcribing and used that understand usage. help with vocabulary development, also translate into tongue. recount podcasts' material improve speaking flow. information learned from podcast applied description images. Students utilized paraphrasing applications complete proofreading It is procedure hone discovered by qualitative data analysis can successfully produce natural using tools, translation services, podcasts. Instructors teach pertinent subjects this kind material. causing other researchers become aware more discoveries.

Язык: Английский

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Leveraging genetic ancestry continuum information to interpolate PRS for admixed populations

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 10, 2024

Abstract The relatively low representation of admixed populations in both discovery and fine-tuning individual-level datasets limits polygenic risk score (PRS) development equitable clinical translation for populations. Under the assumption that most informative PRS weight a homogeneous sample varies linearly an ancestry continuum space, we introduce Genetic Dis tance-assisted Co mbination Pipeline Div erse A ncestrie s ( DiscoDivas ) to interpolate harmonized diverse, especially admixed, ancestries, leveraging multiple weights fine-tuned within single-ancestry samples genetic distance. treats as continuous variable does not require shifting between different models when calculating ancestries. We generated with current conventional method, i.e. GWAS using matched or similar samples. accuracy comparable higher than approach, greatest advantage exhibited individuals.

Язык: Английский

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Leveraging large-scale datasets and single cell omics data to develop a polygenic score for cisplatin-induced ototoxicity

Human Genomics, Год журнала: 2024, Номер 18(1)

Опубликована: Окт. 8, 2024

Abstract Background Cisplatin-induced ototoxicity (CIO), characterized by irreversible and progressive bilateral hearing loss, is a prevalent adverse effect of cisplatin chemotherapy. Alongside clinical risk factors, genetic variants contribute to CIO genome-wide association studies (GWAS) have highlighted the polygenicity this drug reaction. Polygenic scores (PGS), which integrate information from multiple across genome, offer promising tool for identification individuals who are at higher CIO. Integrating large-scale loss GWAS data with single cell omics holds potential overcome limitations related small sample sizes associated studies, enabling creation PGSs predict risk. Results We utilized murine inner ear nuclei RNA-sequencing (snRNA-seq) develop two polygenic scores: PGS (PGS HL ) biologically informed ). The included only mapped genes that were differentially expressed within cochlear cells showed differential abundance in snRNA-seq post-cisplatin treatment. Evaluation these our target cohort revealed demonstrated superior performance ( P = 5.54 × 10 − 5 relative 2.93 3 was also test 0.04), while did not show significant 0.52). Conclusion This study developed first using dataset filter generated cisplatin-treated data. innovative approach offers new avenues developing pharmacogenomic traits, could implementation tailored therapeutic interventions. Further, facilitated specific may play critical roles These novel insights will guide future research aimed targeted strategies prevent

Язык: Английский

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Methods for multiancestry genome‐wide association study meta‐analysis

Annals of Human Genetics, Год журнала: 2024, Номер unknown

Опубликована: Июль 18, 2024

Abstract Genome‐wide association studies (GWAS) have significantly enhanced our understanding of the genetic basis complex diseases. Despite technological advancements, gaps in remain, partly due to small effect sizes and inadequate coverage variation. Multiancestry GWAS meta‐analysis (MAGMA) addresses these challenges by integrating data from diverse populations, thereby increasing power detect loci improving fine‐mapping resolution identify causal variants across different ancestry groups. This review provides an overview protocols, statistical methods, software MAGMA, as well highlighting some associated with this approach.

Язык: Английский

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