Genome-wide association studies: Utility and limitations for research in physiology.

Physiological systems are subject to interindividual variation encoded by genetics. Genome-wide association studies (GWAS) operate by surveying thousands of genetic variants from a substantial number of individuals and assessing their association to a trait of interest, be it a physiological variable, a molecular phenotype (e.g., gene expression) or even a disease or condition. Through a myriad of methods, GWAS downstream analyses then explore the functional consequences of each variant and attempt to ascertain a causal relationship to the phenotype of interest, as well as to delve into its links to other traits. This type of investigation allows mechanistic insights into physiological functions, pathological disturbances, and shared biological processes between traits (i.e., pleiotropy). An exciting example is the discovery of a new thyroid hormone transporter (SLC17A4) and hormone metabolising enzyme (AADAT) from a GWAS on free thyroxine levels. Therefore, GWAS have substantially contributed with insights into Physiology and have shown to be useful in unveiling the genetic control underlying complex traits and pathological conditions; they will continue to do so with global collaborations and advances in genotyping technology. Finally, the increasing number of trans-ancestry GWAS and initiatives to include ancestry diversity in genomics will boost the power for discoveries, making them also applicable to non-European populations. Abstract figure legend From left to right in the scheme, a significant genetic variant (a dot that crosses the significance line on the Manhattan plot) is associated with a target disease. Still, it may present a larger effect size on intermediate physiological variables related to the studied condition (demonstrated by the slope on each graph on the right). Therefore, genome-wide association studies (GWAS) allow mechanistic insights into physiological functions, which is important to fulfil gaps in the molecular mechanisms modulating physiology and investigate the shared biology between physiological traits and diseases. This article is protected by copyright. All rights reserved.