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

Admix-kit: an integrated toolkit and pipeline for genetic analyses of admixed populations DOI Creative Commons
Kangcheng Hou, Stephanie M. Gogarten, Joohyun Kim

et al.

Bioinformatics, Journal Year: 2024, Volume and Issue: 40(4)

Published: March 15, 2024

Abstract Summary Admixed populations, with their unique and diverse genetic backgrounds, are often underrepresented in studies. This oversight not only limits our understanding but also exacerbates existing health disparities. One major barrier has been the lack of efficient tools tailored for special challenges studies admixed populations. Here, we present admix-kit, an integrated toolkit pipeline analyses Admix-kit implements a suite methods to facilitate genotype phenotype simulation, association testing, architecture inference, polygenic scoring Availability implementation package is open-source available at https://github.com/KangchengHou/admix-kit. Additionally, users can use designed simulation https://github.com/UW-GAC/admix-kit_workflow.

Language: Английский

Citations

5
Integrated clinical risk prediction of type 2 diabetes with a multifactorial polygenic risk score DOI Creative Commons
Scott C. Ritchie, Henry J. Taylor,

Yujian Liang

et al.

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

Published: Aug. 22, 2024

Combining information from multiple GWASs for a disease and its risk factors has proven powerful approach development of polygenic scores (PRSs). This may be particularly useful type 2 diabetes (T2D), highly heterogeneous where the additional predictive value PRS is unclear. Here, we use meta-scoring to develop metaPRS T2D that incorporated genome-wide associations both European non-European genetic ancestries factors. We evaluated performance this benchmarked it against existing in 620,059 participants 50,572 cases amongst six diverse UK Biobank, INTERVAL, All Us Research Program, Singapore Multi-Ethnic Cohort. show our was most predicting population-based cohorts had comparable top ancestry-specific PRS, highlighting transferability. In stronger power 10-year than all individual apart BMI biomarkers dysglycemia. The modestly improved stratification QDiabetes prediction, when prioritising individuals blood tests Overall, present transferrable demonstrate potential incrementally improve prediction into guideline-recommended screening with clinical score.

Language: Английский

Citations

5
Leveraging haplotype information in heritability estimation and polygenic prediction DOI Creative Commons
Jonas Meisner, Michael E. Benros, Simon Rasmussen

et al.

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

Published: Jan. 2, 2025

Polygenic prediction has yet to make a major clinical breakthrough in precision medicine and psychiatry, where the application of polygenic risk scores is expected improve decision-making. Most widely used approaches for estimating are based on summary statistics from external large-scale genome-wide association studies, which rely assumptions matching data distributions. This may hinder impact modern diverse populations due small differences genetic architectures. Reference-free estimators instead genomic best linear unbiased predictions model population interest directly. We introduce framework, named hapla, with novel algorithm clustering haplotypes phased genotype estimate heritability perform reference-free complex traits. utilize inferred haplotype clusters compute accurate estimates simulation study iPSYCH2012 case-cohort depression disorders schizophrenia. demonstrate that our haplotype-based approach robustly outperforms standard genotype-based approaches, can help pave way future psychiatry. Here authors develop framework leverage information through estimation prediction. Their disease more accurately than existing methods, paving advancements personalized medicine.

Language: Английский

Citations

0
Breaking research silos to achieve equitable precision medicine in rheumatology DOI
Hannah C. Ainsworth, DeAnna Baker Frost, S. Sam Lim

et al.

Nature Reviews Rheumatology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 10, 2025

Language: Английский

Citations

0
Proteogenomic analysis reveals Arp 2/3 complex as a common molecular mechanism in high risk pancreatic cysts and pancreatic cancer DOI Creative Commons
A. K. M. Firoj Mahmud,

Dina Gamaleldin Mansour Aly,

Yelin Zhao

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 31, 2025

Pancreatic cysts, particularly intraductal papillary mucinous neoplasms (IPMNs), pose a potential risk for progressing to pancreatic cancer (PC). This study investigates the genetic architecture of benign cysts and its connection PC using genome-wide association studies (GWAS). The discovery GWAS identified significant variants associated with specifically rs142409042 variant near OPCML gene. A pairwise comparing revealed rs7190458 BCAR1 CTRB1 genes. Further analysis genes highlighted Actin Related Protein (Arp) 2/3 complex as potentially important molecular mechanism connecting PC. Arp2/3 complex-associated were significantly upregulated in PC, suggesting their role malignant transformation cysts. Differential expression these was observed across various cell types indicating involvement tumor microenvironment. These findings suggest that can serve biomarkers predicting opening new avenues targeted therapies early detection strategies.

Language: Английский

Citations

0
Associations of polygenic scores and developmental trajectories of externalizing behaviors DOI
Alyssa Brooke Sasia, Katherine Jonas, Monika A. Waszczuk

et al.

Development and Psychopathology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 15

Published: Jan. 31, 2025

Polygenic scores (PGSs) have garnered increasing attention in the clinical sciences due to their robust prediction signals for psychopathology, including externalizing (EXT) behaviors. However, studies leveraging PGSs rarely accounted phenotypic and developmental heterogeneity EXT outcomes. We used National Longitudinal Study of Adolescent Adult Health (analytic N = 4,416), spanning ages 13 41, examine associations between trajectories antisocial behaviors (ASB) substance use (SUB) identified via growth mixture modeling. Four ASB were identified: High Decline (3.6% sample), Moderate (18.9%), Adolescence-Peaked (10.6%), Low (67%), while three SUB: Use (35.2%), Typical (41.7%), (23%). consistently associated with persistent SUB (High Use, respectively), relative comparison groups. also trajectory SUB, group. Results suggest may be sensitive typologies EXT, where are more strongly predictive chronicity addition (or possibly rather than) absolute severity.

Language: Английский

Citations

0
Polygenic scores for disease risk are not associated with clinical outcomes in Parkinson's disease DOI Creative Commons
Manuela Tan, Hirotaka Iwaki, Sara Bandrés‐Ciga

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract Polygenic risk scores (PRS) in Parkinson’s disease (PD) are associated with risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants biological pathways or cell types. Here, we investigated 8 regions open chromatin using PRS: alpha-synuclein pathway, adaptive immunity, innate lysosomal pathway1, endocytic membrane-trafficking mitochondrial microglial single nucleotide polymorphisms (SNPs), and monocyte SNPs. We analysed 7,402 PD patients across 18 ‘in-person’ cohorts, 6,717 from the online Fox Insight study. did not find any significant associations between PRSs clinical outcomes PD. Though this may be due a lack statistical power limited sample size, it also suggest that genetic architecture sporadic is different genetics progression outcomes.

Language: Английский

Citations

0
MUSSEL: Enhanced Bayesian Polygenic Risk Prediction Leveraging Information across Multiple Ancestry Groups DOI Creative Commons
Jin Jin, Jianan Zhan, Jingning Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: April 13, 2023

Polygenic risk scores (PRS) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists substantial gap across different populations. We propose MUSSEL, method for ancestry-specific polygenic prediction that borrows information in the summary statistics from genome-wide association studies (GWAS) multiple ancestry groups. MUSSEL conducts Bayesian hierarchical modeling under MUltivariate Spike-and-Slab model effect-size distribution incorporates an Ensemble Learning step using super learner to combine tuning parameter settings In our simulation data analyses 16 four distinct studies, totaling 5.7 million participants with ancestral diversity, shows compared alternatives. The method, example, has average gain R

Language: Английский

Citations

11
Highly parameterized polygenic scores tend to overfit to population stratification via random effects DOI Creative Commons
Alan J. Aw, Jeremy F. McRae, Elior Rahmani

et al.

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

Published: Jan. 29, 2024

Abstract Polygenic scores (PGSs), increasingly used in clinical settings, frequently include many genetic variants, with performance typically peaking at thousands of variants. Such highly parameterized PGSs often variants that do not pass a genome-wide significance threshold. We propose mathematical perspective renders the effects these nonsignificant random rather than causal, randomness capturing population structure. devise methods to assess variant effect and stratification bias. Applying 141 traits from UK Biobank, we find that, for PGSs, non-significant are considerably random, extent associated degree overfitting structure discovery cohort. Our findings explain why simultaneously have superior cohort-specific limited generalizability, suggesting critical need tests PGS evaluation. Supporting code dashboard available https://github.com/songlab-cal/StratPGS .

Language: Английский

Citations

4
Promoting equity in polygenic risk assessment through global collaboration DOI
Iftikhar J. Kullo

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(9), P. 1780 - 1787

Published: Aug. 5, 2024

Language: Английский

Citations

4