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1. A unifying framework for joint trait analysis under a non-infinitesimal model

   https://doi.org/10.1093/bioinformatics/bty254  

   Johnson, Ruth ; Shi, Huwenbo ; Pasaniuc, Bogdan ; Sankararaman, Sriram ( June 2018 , Bioinformatics)

   A large proportion of risk regions identified by genome-wide association studies (GWAS) are shared across multiple diseases and traits. Understanding whether this clustering is due to sharing of causal variants or chance colocalization can provide insights into shared etiology of complex traits and diseases.

   In this work, we propose a flexible, unifying framework to quantify the overlap between a pair of traits called UNITY (Unifying Non-Infinitesimal Trait analYsis). We formulate a Bayesian generative model that relates the overlap between pairs of traits to GWAS summary statistic data under a non-infinitesimal genetic architecture underlying each trait. We propose a Metropolis–Hastings sampler to compute the posterior density of the genetic overlap parameters in this model. We validate our method through comprehensive simulations and analyze summary statistics from height and body mass index GWAS to show that it produces estimates consistent with the known genetic makeup of both traits.

   The UNITY software is made freely available to the research community at: https://github.com/bogdanlab/UNITY.

   Supplementary data are available at Bioinformatics online.

    

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2. Applying meta-analysis to genotype-tissue expression data from multiple tissues to identify eQTLs and increase the number of eGenes

   https://doi.org/10.1093/bioinformatics/btx227  

   Duong, Dat ; Gai, Lisa ; Snir, Sagi ; Kang, Eun Yong ; Han, Buhm ; Sul, Jae Hoon ; Eskin, Eleazar ( July 2017 , Bioinformatics)

   There is recent interest in using gene expression data to contextualize findings from traditional genome-wide association studies (GWAS). Conditioned on a tissue, expression quantitative trait loci (eQTLs) are genetic variants associated with gene expression, and eGenes are genes whose expression levels are associated with genetic variants. eQTLs and eGenes provide great supporting evidence for GWAS hits and important insights into the regulatory pathways involved in many diseases. When a significant variant or a candidate gene identified by GWAS is also an eQTL or eGene, there is strong evidence to further study this variant or gene. Multi-tissue gene expression datasets like the Gene Tissue Expression (GTEx) data are used to find eQTLs and eGenes. Unfortunately, these datasets often have small sample sizes in some tissues. For this reason, there have been many meta-analysis methods designed to combine gene expression data across many tissues to increase power for finding eQTLs and eGenes. However, these existing techniques are not scalable to datasets containing many tissues, like the GTEx data. Furthermore, these methods ignore a biological insight that the same variant may be associated with the same gene across similar tissues.

   We introduce a meta-analysis model that addresses these problems in existing methods. We focus on the problem of finding eGenes in gene expression data from many tissues, and show that our model is better than other types of meta-analyses.

   Source code is at https://github.com/datduong/RECOV.

   Supplementary data are available at Bioinformatics online.

    

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3. 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)

   Many 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.

   Here, 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.

   Our source code is available at https://github.com/lgai/CONFIT.

   Supplementary data are available at Bioinformatics online.

    

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4. GSEL: a fast, flexible python package for detecting signatures of diverse evolutionary forces on genomic regions

   https://doi.org/10.1093/bioinformatics/btad037  

   Abraham, Abin ; Labella, Abigail L. ; Benton, Mary Lauren ; Rokas, Antonis ; Capra, John A. ; Marschall, ed., Tobias ( January 2023 , Bioinformatics)

   GSEL is a computational framework for calculating the enrichment of signatures of diverse evolutionary forces in a set of genomic regions. GSEL can flexibly integrate any sequence-based evolutionary metric and analyze sets of human genomic regions identified by genome-wide assays (e.g. GWAS, eQTL, *-seq). The core of GSEL’s approach is the generation of empirical null distributions tailored to the allele frequency and linkage disequilibrium structure of the regions of interest. We illustrate the application of GSEL to variants identified from a GWAS of body mass index, a highly polygenic trait.

   GSEL is implemented as a fast, flexible and user-friendly python package. It is available with demonstration data at https://github.com/abraham-abin13/gsel_vec.

   Supplementary 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.)

   Genome-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.

   This 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.

   The source code and data are available at https://github.com/amioamo/TDS.

    

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