GWAS advancements to investigate disease associations and biological mechanisms

Abstract

Genome-wide association studies (GWAS) have been instrumental in elucidating the genetic architecture of various traits and diseases. Despite the success of GWAS, inherent limitations such as identifying rare and ultra-rare variants, the potential for spurious associations and pinpointing causative agents can undermine diagnostic capabilities. This review provides an overview of GWAS and highlights recent advances in genetics that employ a range of methodologies, including whole-genome sequencing (WGS), Mendelian randomisation (MR), the Pangenome's high-quality Telomere-to-Telomere (T2T)-CHM13 panel and the Human BioMolecular Atlas Program (HuBMAP), as potential enablers of current and future GWAS research. The state of the literature demonstrates the capabilities of these techniques to enhance the statistical power of GWAS. WGS, with its comprehensive approach, captures the entire genome, surpassing the capabilities of the traditional GWAS technique focused on predefined single nucleotide polymorphism sites. The Pangenome's T2T-CHM13 panel, with its holistic approach, aids in the analysis of regions with high sequence identity, such as segmental duplications. MR has advanced causative inference, improving clinical diagnostics and facilitating definitive conclusions. Furthermore, spatial biology techniques such as HuBMAP enable 3D molecular mapping of tissues at single-cell resolution, offering insights into pathology of complex traits. This study aimed to elucidate and advocate for the increased application of these technologies, highlighting their potential to shape the future of GWAS research.