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Prioritization of disease genes from GWAS using ensemble-based positive-unlabeled learning


A primary challenge in understanding disease biology from genome-wide association studies (GWAS) arises from the inability to directly implicate causal genes from association data. Integration of multiple-omics data sources potentially provides important functional links between associated variants and candidate genes. Machine-learning is well-positioned to take advantage of a variety of such data and provide a solution for the prioritization of disease genes. Yet, classical positive-negative classifiers impose strong limitations on the gene prioritization procedure, such as a lack of reliable non-causal genes for training. Here, we developed a novel gene prioritization tool—Gene Prioritizer (GPrior). It is an ensemble of five positive-unlabeled bagging classifiers (Logistic Regression, Support Vector Machine, Random Forest, Decision Tree, Adaptive Boosting), that treats all genes of unknown relevance as an unlabeled set. GPrior selects an optimal composition of algorithms to tune the model for each specific phenotype. Altogether, GPrior fills an important niche of methods for GWAS data post-processing, significantly improving the ability to pinpoint disease genes compared to existing solutions.

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Fig. 1: GPrior ensemble positive-unlabeled learning framework.
Fig. 2: Gene prioritization for inflammatory bowel disease GWAS.
Fig. 3: Gene prioritization for coronary artery disease GWAS.
Fig. 4: Gene prioritization for schizophrenia GWAS.

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The authors would like to thank Dr. Alexey Sergushichev (ITMO University) and Dr. Maxim Artyomov (Washington University in St. Louis) for helpful discussions.


N.K. was supported by the grant of the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2020-901).

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Correspondence to Mark J. Daly or Mykyta Artomov.

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Kolosov, N., Daly, M.J. & Artomov, M. Prioritization of disease genes from GWAS using ensemble-based positive-unlabeled learning. Eur J Hum Genet 29, 1527–1535 (2021).

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