Dataset Information

Reaching the End-Game for GWAS: Machine Learning Approaches for the Prioritization of Complex Disease Loci.

ABSTRACT: Genome-wide association studies (GWAS) have revealed thousands of genetic loci that underpin the complex biology of many human traits. However, the strength of GWAS - the ability to detect genetic association by linkage disequilibrium (LD) - is also its limitation. Whilst the ever-increasing study size and improved design have augmented the power of GWAS to detect effects, differentiation of causal variants or genes from other highly correlated genes associated by LD remains the real challenge. This has severely hindered the biological insights and clinical translation of GWAS findings. Although thousands of disease susceptibility loci have been reported, causal genes at these loci remain elusive. Machine learning (ML) techniques offer an opportunity to dissect the heterogeneity of variant and gene signals in the post-GWAS analysis phase. ML models for GWAS prioritization vary greatly in their complexity, ranging from relatively simple logistic regression approaches to more complex ensemble models such as random forests and gradient boosting, as well as deep learning models, i.e., neural networks. Paired with functional validation, these methods show important promise for clinical translation, providing a strong evidence-based approach to direct post-GWAS research. However, as ML approaches continue to evolve to meet the challenge of causal gene identification, a critical assessment of the underlying methodologies and their applicability to the GWAS prioritization problem is needed. This review investigates the landscape of ML applications in three parts: selected models, input features, and output model performance, with a focus on prioritizations of complex disease associated loci. Overall, we explore the contributions ML has made towards reaching the GWAS end-game with consequent wide-ranging translational impact.

SUBMITTER: Nicholls HL

PROVIDER: S-EPMC7174742 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Reaching the End-Game for GWAS: Machine Learning Approaches for the Prioritization of Complex Disease Loci.

Nicholls Hannah L HL John Christopher R CR Watson David S DS Munroe Patricia B PB Barnes Michael R MR Cabrera Claudia P CP

Frontiers in genetics 20200415

Genome-wide association studies (GWAS) have revealed thousands of genetic loci that underpin the complex biology of many human traits. However, the strength of GWAS - the ability to detect genetic association by linkage disequilibrium (LD) - is also its limitation. Whilst the ever-increasing study size and improved design have augmented the power of GWAS to detect effects, differentiation of causal variants or genes from other highly correlated genes associated by LD remains the real challenge. ...[more]

PMID: 32351543

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Project description:BACKGROUND: Discovering novel disease genes is still challenging for diseases for which no prior knowledge--such as known disease genes or disease-related pathways--is available. Performing genetic studies frequently results in large lists of candidate genes of which only few can be followed up for further investigation. We have recently developed a computational method for constitutional genetic disorders that identifies the most promising candidate genes by replacing prior knowledge by experimental data of differential gene expression between affected and healthy individuals.To improve the performance of our prioritization strategy, we have extended our previous work by applying different machine learning approaches that identify promising candidate genes by determining whether a gene is surrounded by highly differentially expressed genes in a functional association or protein-protein interaction network. RESULTS: We have proposed three strategies scoring disease candidate genes relying on network-based machine learning approaches, such as kernel ridge regression, heat kernel, and Arnoldi kernel approximation. For comparison purposes, a local measure based on the expression of the direct neighbors is also computed. We have benchmarked these strategies on 40 publicly available knockout experiments in mice, and performance was assessed against results obtained using a standard procedure in genetics that ranks candidate genes based solely on their differential expression levels (Simple Expression Ranking). Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene on average at position 17 with an AUC value of 83.7%. CONCLUSION: In this study we could identify promising candidate genes using network based machine learning approaches even if no knowledge is available about the disease or phenotype.

Dataset Information

Reaching the End-Game for GWAS: Machine Learning Approaches for the Prioritization of Complex Disease Loci.

Publications

Reaching the End-Game for GWAS: Machine Learning Approaches for the Prioritization of Complex Disease Loci.

Similar Datasets

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