From GWAS to Function: Using Functional Genomics to Identify the Mechanisms Underlying Complex Diseases

Abstract

Genome-wide association studies (GWAS) have successfully mapped thousands of loci associated with complex traits. These associations could reveal the molecular mechanisms altered in common complex diseases and result in the identification of novel drug targets. However, GWAS have also left a number of outstanding questions. In particular, the majority of disease-associated loci lie in non-coding regions of the genome and, even though they are thought to play a role in gene expression regulation, it is unclear which genes they regulate and in which cell types or physiological contexts this regulation occurs. This has hindered the translation of GWAS findings into clinical interventions. In this review we summarize how these challenges have been addressed over the last decade, with a particular focus on the integration of GWAS results with functional genomics datasets. Firstly, we investigate how the tissues and cell types involved in diseases can be identified using methods that test for enrichment of GWAS variants in genomic annotations. Secondly, we explore how to find the genes regulated by GWAS loci using methods that test for colocalization of GWAS signals with molecular phenotypes such as quantitative trait loci (QTLs). Finally, we highlight potential future research avenues such as integrating GWAS results with single-cell sequencing readouts, designing functionally informed polygenic risk scores (PRS), and validating disease associated genes using genetic engineering. These tools will be crucial to identify new drug targets for common complex diseases.

Learning from Fifteen Years of Genome-Wide Association Studies in Age-Related Macular Degeneration

“…Although eQTL and TWAS studies point out valuable candidates from GWAS loci for further functional studies, it is still mostly unclear by which mechanisms gene expression regulation could influence disease pathogenesis [ 52 , 53 ]. In general, eQTL studies use RNA information from healthy tissues and thus may not provide accurate information for a disease-related situation when pathological damage has occurred for some time possibly causing subsequent molecular alterations never seen in healthy tissue.…”

Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

“…Complex diseases such as cancer and psychiatric disorders are genetic diseases related to multiple genomic variants. Increasing studies have shown that compared with mutations in the coding regions, variations associated with the regulatory mechanisms are more likely to cause diseases related to complex traits [10]. The ne-tuning on the post-transcriptional level is important to gene regulation.…”

Functional polymorphisms and transcriptional analysis in the 5' region of the human serotonin receptor 1B gene (HTR1B) and their associations with psychiatric disorders

“…variations associated with the regulatory mechanisms are more likely to cause diseases related to complex traits [10]. The ne-tuning on the post-transcriptional level is important to gene regulation.…”