Massively parallel variant-to-function mapping determines functional regulatory variants of non-small cell lung cancer DOI Creative Commons
Congcong Chen, Yang Li, Yayun Gu

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 6, 2025

Genome-wide association studies have identified thousands of genetic variants associated with non-small cell lung cancer (NSCLC), however, it is still challenging to determine the causal and improve disease risk prediction. Here, we applied massively parallel reporter assays perform NSCLC variant-to-function mapping at scale. A total 1249 candidate were evaluated, 30 potential within 12 loci identified. Accordingly, proposed three architectures underlying susceptibility: multiple in a single haplotype block (e.g. 4q22.1), blocks 5p15.33), variant 20q11.23). We developed modified polygenic score using from Chinese populations, improving performance prediction 450,821 Europeans UK Biobank. Our findings not only augment understanding architecture susceptibility but also provide strategy advance stratification. Determining GWAS crucial for mechanisms. authors apply MPRA (NSCLC) scale propose distinct susceptibility.

Language: Английский

Mechanisms linking social media use to adolescent mental health vulnerability DOI Creative Commons
Amy Orben, Adrian Meier, Tim Dalgleish

et al.

Nature Reviews Psychology, Journal Year: 2024, Volume and Issue: 3(6), P. 407 - 423

Published: May 7, 2024

Language: Английский

Citations

28
An ensemble penalized regression method for multi-ancestry polygenic risk prediction DOI Creative Commons
Jingning Zhang, Jianan Zhan, Jin Jin

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 15, 2024

Abstract Great efforts are being made to develop advanced polygenic risk scores (PRS) improve the prediction of complex traits and diseases. However, most existing PRS primarily trained on European ancestry populations, limiting their transferability non-European populations. In this article, we propose a novel method for generating multi-ancestry Polygenic Risk scOres based enSemble PEnalized Regression models (PROSPER). PROSPER integrates genome-wide association studies (GWAS) summary statistics from diverse populations ancestry-specific with improved predictive power minority The uses combination $${{{{{{\mathscr{L}}}}}}}_{1}$$ L 1 (lasso) $${{{{{{\mathscr{L}}}}}}}_{2}$$ 2 (ridge) penalty functions, parsimonious specification parameters across an ensemble step combine generated different parameters. We evaluate performance other methods large-scale simulated real datasets, including those 23andMe Inc., Global Lipids Genetics Consortium, All Us. Results show that can substantially compared alternative wide variety genetic architectures. data analyses, example, increased out-of-sample R 2 continuous by average 70% state-of-the-art Bayesian (PRS-CSx) in African population. Further, is computationally highly scalable analysis large SNP contents many

Language: Английский

Citations

24
MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups DOI Creative Commons
Jin Jin, Jianan Zhan, Jingning Zhang

et al.

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(4), P. 100539 - 100539

Published: April 1, 2024

Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists substantial gap across populations. We propose MUSSEL, method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) multiple ancestry groups via Bayesian hierarchical modeling ensemble learning. In our simulation data analyses four distinct studies, totaling 5.7 million participants with ancestral diversity, MUSSEL shows compared to alternatives. For example, has an average gain R

Language: Английский

Citations

15
Screening embryos for polygenic disease risk: a review of epidemiological, clinical, and ethical considerations DOI Creative Commons
Antonio Capalbo,

G. de Wert,

Heidi Mertes

et al.

Human Reproduction Update, Journal Year: 2024, Volume and Issue: 30(5), P. 529 - 557

Published: May 28, 2024

The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural and aneuploidy. Recent advances have made genome-wide genotyping IVF feasible affordable, raising the possibility screening for their risk polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called embryo (PES; also PGT-P), it is already available patients some countries. Several articles studied epidemiological, clinical, ethical perspectives on PES; however, comprehensive, principled review emerging field missing.

Language: Английский

Citations

11
Evaluating Performance and Agreement of Coronary Heart Disease Polygenic Risk Scores DOI
Sarah Abramowitz, Kristin Boulier, Karl Keat

et al.

JAMA, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

Importance Polygenic risk scores (PRSs) for coronary heart disease (CHD) are a growing clinical and commercial reality. Whether existing provide similar individual-level assessments of susceptibility remains incompletely characterized. Objective To characterize the agreement CHD PRSs that perform similarly at population level. Design, Setting, Participants Cross-sectional study participants from diverse backgrounds enrolled in All Us Research Program (AOU), Penn Medicine BioBank (PMBB), University California, Los Angeles (UCLA) ATLAS Precision Health Biobank with electronic health record genotyping data. Exposures published new developed separately testing samples. Main Outcomes Measures performed population-level prediction were identified by comparing calibration discrimination models prevalent CHD. Individual-level was tested intraclass correlation coefficient (ICC) Light κ. Results A total 48 calculated 171 095 AOU participants. The mean (SD) age 56.4 (16.8) years. 104 947 (61.3%) female. 35 590 (20.8%) most genetically to an African reference population, 29 801 (17.4%) admixed American 100 493 (58.7%) European remaining Central/South Asian, East Middle Eastern populations. There 17 589 (10.3%) 153 506 without (89.7%) When included model CHD, 46 had practically equivalent Brier area under receiver operator curves (region practical equivalence ±0.02). Twenty percent least 1 score both top bottom 5% risk. Continuous individual predictions poor (ICC, 0.373 [95% CI, 0.372-0.375]). κ, used evaluate consistency assignment, did not exceed 0.56. Analysis among 41 193 PMBB 53 092 yielded different sets scores, which also lacked agreement. Conclusions Relevance level demonstrated highly variable estimates Recognizing may generate incongruent estimates, effective implementation will require refined statistical methods quantify uncertainty strategies communicate this patients clinicians.

Language: Английский

Citations

8
Genetic risk score for Alzheimer's disease predicts brain volume differences in mid and late life in UK biobank participants DOI Creative Commons
Peter T. Buto, Jingxuan Wang, Renaud La Joie

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(3), P. 1978 - 1987

Published: Jan. 6, 2024

Abstract INTRODUCTION We estimated the ages when associations between Alzheimer's disease (AD) genes and brain volumes begin among middle‐aged older adults. METHODS Among 45,616 dementia‐free participants aged 45–80, linear regressions tested whether genetic risk score for AD (AD‐GRS) had age‐dependent with 38 regional magnetic resonance imaging volumes. Models were adjusted sex, assessment center, ancestry, intracranial volume. RESULTS AD‐GRS modified effect of age (per decade) on amygdala (−0.41 mm 3 [−0.42, −0.40]); hippocampus (−0.45 [−0.45, −0.44]), nucleus accumbens (−0.55 [−0.56, −0.54]), thalamus (−0.38 [−0.39, −0.37]), medial orbitofrontal cortex (−0.23 [−0.24, −0.22]). Trends began by 45 thalamus, 48 hippocampus, 51 amygdala, 53 cortex. An excluding apolipoprotein E ( APOE ) was additionally associated entorhinal middle temporal cortices. DISCUSSION other that increase predict lower hippocampal age.

Language: Английский

Citations

6
Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer’s Disease DOI Open Access
Oneil G. Bhalala, Rosie Watson, Nawaf Yassi

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1231 - 1231

Published: Jan. 19, 2024

Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden morbidity and mortality. Diagnosing before symptoms are established clinically challenging, but would provide therapeutic windows disease-modifying interventions. Blood biomarkers, including genetics, proteins metabolites, emerging as powerful predictors at various timepoints within course, preclinical stage. In this review, we discuss recent advances in such blood biomarkers determining risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their profile. summarize studies analyzing protein well report proteomic- metabolomic-based prediction models. Finally, combination multi-omic potentially be used memory clinics diagnosis to assess dynamic an individual has developing dementia.

Language: Английский

Citations

6
Managing differential performance of polygenic risk scores across groups: Real-world experience of the eMERGE Network DOI Creative Commons
Anna Lewis,

Rex L Chisholm,

John J. Connolly

et al.

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(6), P. 999 - 1005

Published: April 29, 2024

Language: Английский

Citations

6
Genome-wide association testing beyond SNPs DOI
Laura Harris, Ellen M. McDonagh, Xiaolei Zhang

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 7, 2024

Language: Английский

Citations

6
Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction DOI Creative Commons
Kristia Yiangou, Nasim Mavaddat, Joe Dennis

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 13, 2024

The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer prediction. However, evaluation of the PRS313 across different European populations which could influence estimation has not been performed. Here, we explored distribution using genotype data from 94,072 females without cancer, European-ancestry 21 countries participating in Breast Cancer Association Consortium (BCAC) and 225,105 female participants UK Biobank. mean differed markedly countries, being highest south-eastern Europe lowest north-western Europe. Using overall to categorise individuals leads overestimation underestimation some respectively. Adjustment principal components explained most observed heterogeneity PRS. Country-specific PRS distributions may be used calibrate categories countries.

Language: Английский

Citations

5