Exploring the use of machine and deep learning in genome-wide association studies: a comprehensive review

Abstract

The advent of high-throughput sequencing technologies has generated increasingly large and complex genomic datasets, necessitating analytical approaches capable of capturing high-dimensional and potentially nonlinear genetic interactions. This situation has significantly impacted the entire field of Genome-Wide Association Study (GWAS), whose primary goal is the identification of genomic traits and variants that are statistically associated with the risk of a disease. However, traditional GWAS methods may show reduced performance when applied to highly polygenic and nonlinear genetic architectures. Computational strategies from Artificial Intelligence (AI) and, in particular, from machine- and deep-learning may provide a powerful tool to overcome such limitations, especially by capturing nonlinear interactions and complex hidden regularities in large-scale data, which traditional GWAS approaches might overlook. To date, only a few approaches have been introduced and systematically assessed. In this review, we describe the main characteristics and limitations of standard statistical approaches for GWAS, the main uses of AI methods in computational genomics, and recent attempts to leverage AI strategies in GWAS. Particular attention will be devoted to key issues, such as the interpretability of methods and results, and the curse of dimensionality. More specifically, the review presents 30 methods designed to leverage AI in GWAS, as well as presenting a comprehensive set of evaluation metrics for their performance, also providing references to the most frequently used databases, and biobanks. Overall, this work may serve as a starting point for both dry- and wet-lab researchers, aiming to extract deeper insights from genomic data by moving beyond traditional linear additive assumptions, and leveraging large-scale datasets through AI-driven approaches.