Regulatory single nucleotide polymorphisms in the human 5-HT2A receptor: Functional properties and disease risks

The serotonin (5-HT) 5-HT2A receptor is known to play an important role in the pathophysiology and treatment of various psychiatric diseases including major depressive disorder and schizophrenia. Antidepressants have been found to down-regulate the 5-HT2A receptor, which may play a role in their therapeutic benefits. Furthermore, expression of the human 5-HT2A receptor has been shown to be altered in patients suffering from a variety of mood disorders, including major depressive disorder. Such alterations may be due to genetic variations in the regulatory region of the 5-HT2A receptor gene (HTR2A). Genetic variations, specifically single nucleotide polymorphisms (SNPs), within the 5' untranslated regulatory region of the gene may alter transcription efficiency and ultimately lead to an increase or decrease of 5-HT2A receptor expression.; In this study, functional analysis was conducted on nine naturally occurring SNPs in the regulatory region of HTR2A using an in vitro reporter gene assay. The most common SNP in the regulatory region (-1438A/G), which has been examined in over 100 disease association studies, was found to be in linkage disequilibrium with two minor SNPs in the regulatory region. These minor SNPs altered the functional consequences of the major SNP in both in vitro assays and in an endogenous system. A precedent has been set in psychiatric association studies of HTR2A to examine this common -1438 A/G polymorphism. However, the current work shows that functional effects of this common SNP are modified by an additional regulatory SNP, thus emphasizing the critical need to incorporate more advanced analyses exploring epistasis, in genetic studies of the 5-HT2A receptor.