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Identification of causal noncoding single nucleotide polymorphisms (SNPs) is important for maximizing the knowledge dividend from human genome-wide association studies (GWAS). Recently, diverse machine learning-based methods have been used for functional SNP identification; however, this task remains a fundamental challenge in computational biology. We report CERENKOV3, a machine learning pipeline that leverages clustering-derived and molecular network-derived features to improve prediction accuracy of regulatory SNPs (rSNPs) in the context of post-GWAS analysis. The clustering-derived feature, locus size (number of SNPs in the locus), derives from our locus partitioning procedure and represents the sizes of clusters based on SNP locations. We generated two molecular network-derived features from representation learning on a network representing SNP-gene and gene-gene relations. Based on empirical studies using a ground-truth SNP dataset, CERENKOV3 significantly improves rSNP recognition performance in AUPRC, AUROC, and AVGRANK (a locus-wise rank-based measure of classification accuracy we previously proposed).

To achieve the provision of personalized medicine, it is very important to investigate the relationship between diseases and human genomes. For this purpose, large-scale genetic studies such as genome-wide association studies are often conducted, but there is a risk of identifying individuals if the statistics are released as they are. In this study, we propose new efficient differentially private methods for a transmission disequilibrium test, which is a family-based association test. Existing methods are computationally intensive and take a long time even for a small cohort. Moreover, for approximation methods, sensitivity of the obtained values is not guaranteed. We present an exact algorithm with a time complexity of 𝒪(nm) for a dataset containing n families and m single nucleotide polymorphisms (SNPs). We also propose an approximation algorithm that is faster than the exact one and prove that the obtained scores’ sensitivity is 1. From our experimental results, we demonstrate that our exact algorithm is 10, 000 times faster than existing methods for a small cohort with 5, 000 SNPs. The results also indicate that the proposed method is the first in the world that can be applied to a large cohort, such as those with 10⁶ SNPs. In addition, we examine a suitable dataset to apply our approximation algorithm. Supplementary materials are available at https://github.com/ay0408/DP-trio-TDT.

To address the lack of statistical power and interpretability of genome-wide association studies (GWAS), gene-level analyses combine the p-values of individual single nucleotide polymorphisms (SNPs) into gene statistics. However, using all SNPs mapped to a gene, including those with low association scores, can mask the association signal of a gene.

We therefore propose a new two-step strategy, consisting in first selecting the SNPs most associated with the phenotype within a given gene, before testing their joint effect on the phenotype. The recently proposed kernelPSI framework for kernel-based post-selection inference makes it possible to model non-linear relationships between features, as well as to obtain valid p-values that account for the selection step.

In this paper, we show how we adapted kernelPSI to the setting of quantitative GWAS, using kernels to model epistatic interactions between neighboring SNPs, and post-selection inference to determine the joint effect of selected blocks of SNPs on a phenotype. We illustrate this tool on the study of two continuous phenotypes from the UKBiobank.

We show that kernelPSI can be successfully used to study GWAS data and detect genes associated with a phenotype through the signal carried by the most strongly associated regions of these genes. In particular, we show that kernelPSI enjoys more statistical power than other gene-based GWAS tools, such as SKAT or MAGMA.

kernelPSI is an effective tool to combine SNP-based and gene-based analyses of GWAS data, and can be used successfully to improve both statistical performance and interpretability of GWAS.

Genome-wide association studies (GWAS) have been successful in facilitating the understanding of genetic architecture behind human diseases, but this approach faces many challenges. To identify disease-related loci with modest to weak effect size, GWAS requires very large sample sizes, which can be computational burdensome. In addition, the interpretation of discovered associations remains difficult. PrediXcan was developed to help address these issues. With built in SNP-expression models, PrediXcan is able to predict the expression of genes that are regulated by putative expression quantitative trait loci (eQTLs), and these predicted expression levels can then be used to perform gene-based association studies. This approach reduces the multiple testing burden from millions of variants down to several thousand genes. But most importantly, the identified associations can reveal the genes that are under regulation of eQTLs and consequently involved in disease pathogenesis. In this study, two of the most practical functions of PrediXcan were tested: 1) predicting gene expression, and 2) prioritizing GWAS results. We tested the prediction accuracy of PrediXcan by comparing the predicted and observed gene expression levels, and also looked into some potential influential factors and a filter criterion with the aim of improving PrediXcan performance. As for GWAS prioritization, predicted gene expression levels were used to obtain gene-trait associations, and background regions of significant associations were examined to decrease the likelihood of false positives. Our results showed that 1) PrediXcan predicted gene expression levels accurately for some but not all genes; 2) including more putative eQTLs into prediction did not improve the prediction accuracy; and 3) integrating predicted gene expression levels from the two PrediXcan whole blood models did not eliminate false positives. Still, PrediXcan was able to prioritize GWAS associations that were below the genome-wide significance threshold in GWAS, while retaining GWAS significant results. This study suggests several ways to consider PrediXcan’s performance that will be of value to eQTL and complex human disease research.

We utilized evidence for enhancer-promoter interactions from functional genomics data in order to build biological filters to narrow down the search space for two-way Single Nucleotide Polymorphism (SNP) interactions in Type 2 Diabetes (T2D) Genome Wide Association Studies (GWAS). This has led us to the identification of a reproducible statistically significant SNP pair associated with T2D. As more functional genomics data are being generated that can help identify potentially interacting enhancer-promoter pairs in larger collection of tissues/cells, this approach has implications for investigation of epistasis from GWAS in general.

Noncoding single nucleotide polymorphisms (SNPs) and their target genes are important components of the heritability of diseases and other polygenic traits. Identifying these SNPs and target genes could potentially reveal new molecular mechanisms and advance precision medicine. For polygenic traits, genome-wide association studies (GWAS) are preferred tools for identifying trait-associated regions. However, identifying causal noncoding SNPs within such regions is a difficult problem in computational biology. The DNA sequence context of a noncoding SNP is well-established as an important source of information that is beneficial for discriminating functional from nonfunctional noncoding SNPs. We describe the use of a deep residual network (ResNet)-based model—entitled Res2s2aM—that fuses anking DNA sequence information with additional SNP annotation information to discriminate functional from nonfunctional noncoding SNPs. On a ground-truth set of disease-associated SNPs compiled from the Genome-wide Repository of Associations between SNPs and Phenotypes (GRASP) database, Res2s2aM improves the prediction accuracy of functional SNPs significantly in comparison to models based only on sequence information as well as a leading tool for post-GWAS noncoding SNP prioritization (RegulomeDB).

The proliferation of sequencing technologies in biomedical research has raised many new privacy concerns. These include concerns over the publication of aggregate data at a genomic scale (e.g. minor allele frequencies, regression coefficients). Methods such as differential privacy can overcome these concerns by providing strong privacy guarantees, but come at the cost of greatly perturbing the results of the analysis of interest. Here we investigate an alternative approach for achieving privacy-preserving aggregate genomic data sharing without the high cost to accuracy of differentially private methods. In particular, we demonstrate how other ideas from the statistical disclosure control literature (in particular, the idea of disclosure risk) can be applied to aggregate data to help ensure privacy. This is achieved by combining minimal amounts of perturbation with Bayesian statistics and Markov Chain Monte Carlo techniques. We test our technique on a GWAS dataset to demonstrate its utility in practice. An implementation is available at https://github.com/seanken/PrivMCMC.

Whole exome and whole genome sequencing are likely to be potent tools in the study of common diseases and complex traits. Despite this promise, some very difficult issues in data management and statistical analysis must be squarely faced. The number of rare variants identified by sequencing is apt to be much larger than the number of common variants encountered in current association studies. The low frequencies of rare variants alone will make association testing difficult. This article extends the penalized regression framework for model selection in genome-wide association data to sequencing data with both common and rare variants. Previous research has shown that lasso penalties discourage irrelevant predictors from entering a model. The Euclidean penalties dealt with here group variants by gene or pathway. Pertinent biological information can be incorporated by calibrating penalties by weights. The current paper examines some of the tradeoffs in using pure lasso penalties, pure group penalties, and mixtures of the two types of penalty. All of the computational and statistical advantages of lasso penalized estimation are retained in this richer setting. The overall strategy is implemented in the free statistical genetics analysis software MENDEL and illustrated on both simulated and real data.

Genome Wide Association (GWA) studies resulted in discovery of genetic variants underlying several complex diseases including Chron's disease and age-related macular degeneration (AMD). Still geneticists find that in majority of studies the size of the effect even if it is significant tends to be very small. There are several factors contributing to this problem such as rare variants, complex relationships among SNPs (epistatic effect), and heterogeneity of the phenotype. In this work we focus on addressing phenotypic heterogeneity. We introduce the problem of identifying, from GWAS data, separate genotypic markers from overlapping mixtures of clinically indistinguishable phenotypes. We propose a generative model for this scenario and derive an expectation-maximization (EM) procedure to fit the model to data, as well as a novel screening procedure designed to identify skew specific to certain phenotypic regimes. We present results on several simulated datasets as well as preliminary findings in applying the model to type 2 diabetes dataset.

The rapid development of sequencing technologies makes thousands to millions of genetic attributes available for testing associations with various biological traits. Searching this enormous high-dimensional data space imposes a great computational challenge in genome-wide association studies. We introduce a network-based approach to supervise the search for three-locus models of disease susceptibility. Such statistical epistasis networks (SEN) are built using strong pairwise epistatic interactions and provide a global interaction map to search for higher-order interactions by prioritizing genetic attributes clustered together in the networks. Applying this approach to a population-based bladder cancer dataset, we found a high susceptibility three-way model of genetic variations in DNA repair and immune regulation pathways, which holds great potential for studying the etiology of bladder cancer with further biological validations. We demonstrate that our SEN-supervised search is able to find a small subset of three-locus models with significantly high associations at a substantially reduced computational cost.

With the rapid increase in the quality and quantity of data generated by modern high-throughput sequencing techniques, there has been a need for innovative methods able to convert this tremendous amount of data into more accessible forms. Networks have been a corner stone of this movement, as they are an intuitive way of representing interaction data, yet they offer a full set of sophisticated statistical tools to analyze the phenomena they model. We propose a novel approach to reveal and analyze pleiotropic and epistatic effects at the genome-wide scale using a bipartite network composed of human diseases, phenotypic traits, and several types of predictive elements (i.e. SNPs, genes, or pathways). We take advantage of publicly available GWAS data, gene and pathway databases, and more to construct networks different levels of granularity, from common genetic variants to entire biological pathways. We use the connections between the layers of the network to approximate the pleiotropy and epistasis effects taking place between the traits and the predictive elements. The global graph-theory based quantitative methods reveal that the levels of pleiotropy and epistasis are comparable for all types of predictive element. The results of the magnified “glaucoma” region of the network demonstrate the existence of well documented interactions, supported by overlapping genes and biological pathway, and more obscure associations. As the amount and complexity of genetic data increases, bipartite, and more generally multipartite networks that combine human diseases and other physical attributes with layers of genetic information, have the potential to become ubiquitous tools in the study of complex genetic and phenotypic interactions.

The large volume of GWAS data poses great computational challenges for analyzing genetic interactions associated with common human diseases. We propose a computational framework for characterizing epistatic interactions among large sets of genetic attributes in GWAS data. We build the human phenotype network (HPN) and focus around a disease of interest. In this study, we use the GLAUGEN glaucoma GWAS dataset and apply the HPN as a biological knowledge-based filter to prioritize genetic variants. Then, we use the statistical epistasis network (SEN) to identify a significant connected network of pairwise epistatic interactions among the prioritized SNPs. These clearly highlight the complex genetic basis of glaucoma. Furthermore, we identify key SNPs by quantifying structural network characteristics. Through functional annotation of these key SNPs using Biofilter, a software accessing multiple publicly available human genetic data sources, we find supporting biomedical evidences linking glaucoma to an array of genetic diseases, proving our concept. We conclude by suggesting hypotheses for a better understanding of the disease.

Genome-wide association studies (GWAS) are an important tool for the study of complex disease genetics. Decisions regarding the quality control (QC) procedures employed as part of a GWAS can have important implications on the results and their biological interpretation. Many GWAS have been conducted predominantly in cohorts of European ancestry, but many initiatives aim to increase the representation of diverse ancestries in genetic studies. The question of how these data should be combined and the consequences that genetic variation across ancestry groups might have on GWAS results warrants further investigation. In this study, we focus on several commonly used methods for combining genetic data across diverse ancestry groups and the impact these decisions have on the outcome of GWAS summary statistics. We ran GWAS on two binary phenotypes using ancestry-specific, multi-ancestry mega-analysis, and meta-analysis approaches. We found that while multi-ancestry mega-analysis and meta-analysis approaches can aid in identifying signals shared across ancestries, they can diminish the signal of ancestry-specific associations and modify their effect sizes. These results demonstrate the potential impact on downstream post-GWAS analyses and follow-up studies. Decisions regarding how the genetic data are combined has the potential to mask important findings that might serve individuals of ancestries that have been historically underrepresented in genetic studies. New methods that consider ancestry-specific variants in conjunction with the shared variants need to be developed.

Precision medicine focuses on developing treatments and preventative strategies tailored to an individual’s genomic profile, lifestyle, and environmental context. The Precision Medicine sessions at the Pacific Symposium on Biocomputing (PSB) have consistently spotlighted progress in this domain. Our 2025 manuscript collection features algorithmic innovations that integrate data across scales and diverse data modalities, presenting novel techniques to derive clinically relevant insights from molecular datasets. These studies highlight recent advances in technology and analytics and their application toward realizing the potential of precision medicine to enhance human health outcomes and extend lifespan.