Testing a polygenic risk score for morphological microglial activation in Alzheimer’s disease and aging DOI Creative Commons
Earvin S. Tio, Timothy J. Hohman, Milos Milic

et al.

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

Published: March 15, 2023

Neuroinflammation and the activation of microglial cells are among earliest events in Alzheimer's disease (AD). However, direct observation microglia living people is not currently possible. Here, we indexed heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis validated post-mortem measure morphological activation. We sought to determine whether PRS (PRS mic ) could augment predictive performance existing AD PRSs late-life cognitive impairment. First, were calculated optimized calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n=450), resampling. Second, optimal was assessed two independent, population-based cohorts (total n=212,237). Our showed no significant improvement power either diagnosis or performance. Finally, explored associations comprehensive set imaging fluid biomarkers ADNI. This revealed some nominal associations, but inconsistent effect directions. While genetic capable indexing neuroinflammatory processes aging highly desirable, more well-powered studies required. Further, biobank-scale would benefit phenotyping proximal improve development phase.

Language: Английский

PUMAS: fine-tuning polygenic risk scores with GWAS summary statistics DOI Creative Commons
Zijie Zhao, Yanyao Yi, Jie Song

et al.

Genome biology, Journal Year: 2021, Volume and Issue: 22(1)

Published: Sept. 6, 2021

Polygenic risk scores (PRSs) have wide applications in human genetics research, but often include tuning parameters which are difficult to optimize practice due limited access individual-level data. Here, we introduce PUMAS, a novel method fine-tune PRS models using summary statistics from genome-wide association studies (GWASs). Through extensive simulations, external validations, and analysis of 65 traits, demonstrate that PUMAS can perform various model-tuning procedures GWAS effectively benchmark under diverse genetic architecture. Furthermore, show fine-tuned PRSs will significantly improve statistical power downstream analysis.

Language: Английский

Citations

36
Large-scale imputation models for multi-ancestry proteome-wide association analysis DOI Creative Commons
Chong Wu, Zichen Zhang,

Xiaochen Yang

et al.

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

Published: Oct. 9, 2023

Abstract Proteome-wide association studies (PWAS) decode the intricate proteomic landscape of biological mechanisms for complex diseases. Traditional PWAS model training relies heavily on individual-level reference proteomes, thereby restricting its capacity to harness emerging summary-level protein quantitative trait loci (pQTL) data in public domain. Here we introduced a novel framework train models directly from pQTL summary statistics. By leveraging extensive UK Biobank, deCODE, and ARIC studies, applied our approach large-scale European (total n = 88,838 subjects). Furthermore, developed tailored Asian African ancestries by integrating multi-ancestry resources 914 3,042 ancestries). We validated performance through systematic analysis over 700 phenotypes across five major genetic resources. Our results bridge gap between genomics proteomics drug discovery, highlighting protein-phenotype links their transferability diverse ancestries. The are freely available at www.gcbhub.org .

Language: Английский

Citations

6
Ensembled best subset selection using summary statistics for polygenic risk prediction DOI Open Access
Tony Chen, Haoyu Zhang,

Rahul Mazumder

et al.

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

Published: Sept. 26, 2023

Abstract Polygenic risk scores (PRS) enhance population stratification and advance personalized medicine, yet existing methods face a tradeoff between predictive power computational efficiency. We introduce ALL-Sum, fast scalable PRS method that combines an efficient summary statistic-based L 0 2 penalized regression algorithm with ensembling step aggregates estimates from different tuning parameters for improved prediction performance. In extensive large-scale simulations across wide range of polygenicity genome-wide association studies (GWAS) sample sizes, ALL-Sum consistently outperforms popular alternative in terms accuracy, runtime, memory usage. analyze 27 published GWAS statistics 11 complex traits 9 reputable data sources, including the Global Lipids Genetics Consortium, Breast Cancer Association FinnGen, evaluated using individual-level UKBB data. achieves highest accuracy most traits, particularly large sizes. provide as user-friendly command-line software pre-computed reference streamlined user-end analysis.

Language: Английский

Citations

2
Testing a Polygenic Risk Score for Morphological Microglial Activation in Alzheimer’s Disease and Aging DOI
Earvin S. Tio, Timothy J. Hohman, Milos Milic

et al.

Journal of Alzheimer s Disease, Journal Year: 2023, Volume and Issue: 94(4), P. 1549 - 1561

Published: July 11, 2023

Background: Neuroinflammation and the activation of microglial cells are among earliest events in Alzheimer’s disease (AD). However, direct observation microglia living people is not currently possible. Here, we indexed heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis validated post-mortem measure morphological activation. Objective: We sought to determine whether PRS (PRSmic) could augment predictive performance existing AD PRSs late-life cognitive impairment. Methods: First, PRSmic were calculated optimized calibration cohort (Alzheimer’s Disease Neuroimaging Initiative (ADNI), n = 450), resampling. Second, optimal was assessed two independent, population-based cohorts (total 212,237). Finally, explored associations comprehensive set imaging fluid biomarkers ADNI. Results: Our showed no significant improvement power either diagnosis or external cohort. Some nominal found ADNI, but inconsistent effect directions. Conclusion: While genetic capable indexing neuroinflammatory processes aging highly desirable, more well-powered studies required. Further, biobank-scale would benefit phenotyping proximal improve development phase.

Language: Английский

Citations

1
Leveraging genetic correlations and multiple populations to improve genetic risk prediction for non-European populations DOI Creative Commons
Hongyu Zhao, Leqi Xu, Geyu Zhou

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 25, 2023

The disparity in genetic risk prediction accuracy between European and non-European individuals highlights a critical challenge health inequality. To bridge this gap, we introduce JointPRS, novel method that models multiple populations jointly to improve predictions for individuals. JointPRS has three key features. First, it encompasses all diverse accuracy, rather than relying solely on the target population with singular auxiliary group. Second, autonomously estimates leverages chromosome-wise cross-population correlations infer effect sizes of variants. Lastly, provides an auto version comparable performance tuning accommodate situation no validation dataset. Through extensive simulations real data applications 22 quantitative traits four binary East Asian populations, nine one trait African South demonstrate outperforms state-of-art methods, improving both populations.

Language: Английский

Citations

1
Testing a polygenic risk score for morphological microglial activation in Alzheimer’s disease and aging DOI Creative Commons
Earvin S. Tio, Timothy J. Hohman, Milos Milic

et al.

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

Published: March 15, 2023

Neuroinflammation and the activation of microglial cells are among earliest events in Alzheimer's disease (AD). However, direct observation microglia living people is not currently possible. Here, we indexed heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis validated post-mortem measure morphological activation. We sought to determine whether PRS (PRS mic ) could augment predictive performance existing AD PRSs late-life cognitive impairment. First, were calculated optimized calibration cohort (Alzheimer's Disease Neuroimaging Initiative (ADNI), n=450), resampling. Second, optimal was assessed two independent, population-based cohorts (total n=212,237). Our showed no significant improvement power either diagnosis or performance. Finally, explored associations comprehensive set imaging fluid biomarkers ADNI. This revealed some nominal associations, but inconsistent effect directions. While genetic capable indexing neuroinflammatory processes aging highly desirable, more well-powered studies required. Further, biobank-scale would benefit phenotyping proximal improve development phase.

Language: Английский

Citations

0