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1. Finding associated variants in genome-wide association studies on multiple traits

   https://doi.org/10.1093/bioinformatics/bty249  

   Gai, Lisa; Eskin, Eleazar (June 2018, Bioinformatics)

   Abstract MotivationMany variants identified by genome-wide association studies (GWAS) have been found to affect multiple traits, either directly or through shared pathways. There is currently a wealth of GWAS data collected in numerous phenotypes, and analyzing multiple traits at once can increase power to detect shared variant effects. However, traditional meta-analysis methods are not suitable for combining studies on different traits. When applied to dissimilar studies, these meta-analysis methods can be underpowered compared to univariate analysis. The degree to which traits share variant effects is often not known, and the vast majority of GWAS meta-analysis only consider one trait at a time. ResultsHere, we present a flexible method for finding associated variants from GWAS summary statistics for multiple traits. Our method estimates the degree of shared effects between traits from the data. Using simulations, we show that our method properly controls the false positive rate and increases power when an effect is present in a subset of traits. We then apply our method to the North Finland Birth Cohort and UK Biobank datasets using a variety of metabolic traits and discover novel loci. Availability and implementationOur source code is available at https://github.com/lgai/CONFIT. Supplementary informationSupplementary data are available at Bioinformatics online. 

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2. A data-adaptive Bayesian regression approach for polygenic risk prediction

   https://doi.org/10.1093/bioinformatics/btac024  

   Song, Shuang; Hou, Lin; Liu, Jun S.; Schwartz, ed., Russell (January 2022, Bioinformatics)

   Abstract MotivationPolygenic risk score (PRS) has been widely exploited for genetic risk prediction due to its accuracy and conceptual simplicity. We introduce a unified Bayesian regression framework, NeuPred, for PRS construction, which accommodates varying genetic architectures and improves overall prediction accuracy for complex diseases by allowing for a wide class of prior choices. To take full advantage of the framework, we propose a summary-statistics-based cross-validation strategy to automatically select suitable chromosome-level priors, which demonstrates a striking variability of the prior preference of each chromosome, for the same complex disease, and further significantly improves the prediction accuracy. ResultsSimulation studies and real data applications with seven disease datasets from the Wellcome Trust Case Control Consortium cohort and eight groups of large-scale genome-wide association studies demonstrate that NeuPred achieves substantial and consistent improvements in terms of predictive r2 over existing methods. In addition, NeuPred has similar or advantageous computational efficiency compared with the state-of-the-art Bayesian methods. Availability and implementationThe R package implementing NeuPred is available at https://github.com/shuangsong0110/NeuPred. Supplementary informationSupplementary data are available at Bioinformatics online. 

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3. UbE3-APA: a bioinformatic strategy to elucidate ubiquitin E3 ligase activities in quantitative proteomics study

   https://doi.org/10.1093/bioinformatics/btac069  

   Gong, Yao; Chen, Yue; Vitek, ed., Olga (February 2022, Bioinformatics)

   Abstract MotivationUbiquitination is widely involved in protein homeostasis and cell signaling. Ubiquitin E3 ligases are critical regulators of ubiquitination that recognize and recruit specific ubiquitination targets for the final rate-limiting step of ubiquitin transfer reactions. Understanding the ubiquitin E3 ligase activities will provide knowledge in the upstream regulator of the ubiquitination pathway and reveal potential mechanisms in biological processes and disease progression. Recent advances in mass spectrometry-based proteomics have enabled deep profiling of ubiquitylome in a quantitative manner. Yet, functional analysis of ubiquitylome dynamics and pathway activity remains challenging. ResultsHere, we developed a UbE3-APA, a computational algorithm and stand-alone python-based software for Ub E3 ligase Activity Profiling Analysis. Combining an integrated annotation database with statistical analysis, UbE3-APA identifies significantly activated or suppressed E3 ligases based on quantitative ubiquitylome proteomics datasets. Benchmarking the software with published quantitative ubiquitylome analysis confirms the genetic manipulation of SPOP enzyme activity through overexpression and mutation. Application of the algorithm in the re-analysis of a large cohort of ubiquitination proteomics study revealed the activation of PARKIN and the co-activation of other E3 ligases in mitochondria depolarization-induced mitophagy process. We further demonstrated the application of the algorithm in the DIA (data-independent acquisition)-based quantitative ubiquitylome analysis. Availability and implementationSource code and binaries are freely available for download at URL: https://github.com/Chenlab-UMN/Ub-E3-ligase-Activity-Profiling-Analysis, implemented in python and supported on Linux and MS Windows. Supplementary informationSupplementary data are available at Bioinformatics online. 

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4. medna-metadata: an open-source data management system for tracking environmental DNA samples and metadata

   https://doi.org/10.1093/bioinformatics/btac556  

   Kimble, M.; Allers, S.; Campbell, K.; Chen, C.; Jackson, L. M.; King, B. L.; Silverbrand, S.; York, G.; Beard, K.; Robinson, ed., Peter (August 2022, Bioinformatics)

   Abstract MotivationEnvironmental DNA (eDNA), as a rapidly expanding research field, stands to benefit from shared resources including sampling protocols, study designs, discovered sequences, and taxonomic assignments to sequences. High-quality community shareable eDNA resources rely heavily on comprehensive metadata documentation that captures the complex workflows covering field sampling, molecular biology lab work, and bioinformatic analyses. There are limited sources that provide documentation of database development on comprehensive metadata for eDNA and these workflows and no open-source software. ResultsWe present medna-metadata, an open-source, modular system that aligns with Findable, Accessible, Interoperable, and Reusable guiding principles that support scholarly data reuse and the database and application development of a standardized metadata collection structure that encapsulates critical aspects of field data collection, wet lab processing, and bioinformatic analysis. Medna-metadata is showcased with metabarcoding data from the Gulf of Maine (Polinski et al., 2019). Availability and implementationThe source code of the medna-metadata web application is hosted on GitHub (https://github.com/Maine-eDNA/medna-metadata). Medna-metadata is a docker-compose installable package. Documentation can be found at https://medna-metadata.readthedocs.io/en/latest/?badge=latest. The application is implemented in Python, PostgreSQL and PostGIS, RabbitMQ, and NGINX, with all major browsers supported. A demo can be found at https://demo.metadata.maine-edna.org/. Supplementary informationSupplementary data are available at Bioinformatics online. 

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5. Privacy-preserving federated genome-wide association studies via dynamic sampling

   https://doi.org/10.1093/bioinformatics/btad639  

   Wang, Xinyue; Dervishi, Leonard; Li, Wentao; Ayday, Erman; Jiang, Xiaoqian; Vaidya, Jaideep (October 2023, Bioinformatics)

   Nikolski, Macha (Ed.)

   Abstract MotivationGenome-wide association studies (GWAS) benefit from the increasing availability of genomic data and cross-institution collaborations. However, sharing data across institutional boundaries jeopardizes medical data confidentiality and patient privacy. While modern cryptographic techniques provide formal secure guarantees, the substantial communication and computational overheads hinder the practical application of large-scale collaborative GWAS. ResultsThis work introduces an efficient framework for conducting collaborative GWAS on distributed datasets, maintaining data privacy without compromising the accuracy of the results. We propose a novel two-step strategy aimed at reducing communication and computational overheads, and we employ iterative and sampling techniques to ensure accurate results. We instantiate our approach using logistic regression, a commonly used statistical method for identifying associations between genetic markers and the phenotype of interest. We evaluate our proposed methods using two real genomic datasets and demonstrate their robustness in the presence of between-study heterogeneity and skewed phenotype distributions using a variety of experimental settings. The empirical results show the efficiency and applicability of the proposed method and the promise for its application for large-scale collaborative GWAS. Availability and implementationThe source code and data are available at https://github.com/amioamo/TDS. 

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