Genetic Variation and Mendelian Randomization Approaches

Abstract

While genome-wide association studies (GWAS) on levels of nuclear receptors are sparse, the genetics of ligands of these receptors (steroid hormones, thyroid hormones, and liposoluble vitamins) have been extensively studied in GWAS of predominantly European populations. Hundreds of genetic variants across the genome have been associated with serum levels of nuclear receptor ligands, shedding light on the physiology of hormone metabolism. These GWAS findings have been used to explore causal associations of these hormones with complex human traits and diseases in Mendelian randomization (MR) studies, and in studies using polygenic risk scores to quantify the genetic predisposition to higher/lower hormone levels. As such, besides providing insights into hormonal pathophysiology and its causal relationship with clinical complications, GWAS-identified genetic markers could ultimately play an important role in the daily clinical management of patients. As large trans-ethnic GWAS on levels of nuclear receptor ligands emerge, and with the fast advances in genotyping techniques and constant decrease of the genotyping costs, studying an individual’s genetically predicted hormonal profile could be the next step in personalizing the management of patients with pathologies related to nuclear receptors and their ligands.