Gene-Based Association Analysis Suggests Association of HTR2A With Antidepressant Treatment Response in Depressed Patients

Chung-Feng Kao,Eugene Lin,Younger W.-Y. Yu,Po-Hsiu Kuo,Yu-Li Liu,Shih-Jen Tsai,Albert C. Yang

doi:10.3389/fphar.2020.559601

Abstract

The serotonin [5-hydroxytryptamine (5-HT)] system has been implicated in the pathogenesis of major depressive disorder (MDD). Among the 5-HT receptor subtypes, 5-HT2 is one of the major pharmacological therapeutic targets for MDD. There have been inconsistent findings in previous pharmacogenetic studies investigating the antidepressant therapeutic response using one or several 5-HT2A (HTR2A) genetic polymorphisms. By using gene-based association analysis, we hope to identify genetic variants of HTR2A which are related to MDD susceptibility and its antidepressant therapeutic response. 288 HTR2A single nucleotide polymorphisms in MDD susceptibility have been investigated through a case–control (455 MDD patients and 2, 998 healthy controls) study, as well as in antidepressant efficacy (n = 455) in our current research. The 21-item Hamilton Rating Scale for Depression was used to evaluate measures of antidepressant therapeutic efficacy. From two MDD groups in the antidepressant therapeutic response, by using gene-based analyses, we have identified 14 polymorphisms as suggestive markers for therapeutic response (13 for remission and 1 for response) in both meta- and mega-analyses. All of these HTR2A reported polymorphisms did not reach statistical significance in the case–control association study. This current investigation supported the link between HTR2A variants and antidepressant therapeutic response in MDD but not with MDD susceptibility.

Highlights

One of the common and sometimes fatal mental disorders is major depressive disorder (MDD), which is a leading cause of disability worldwide (Moussavi et al, 2007)
One of the possible actions of antidepressant medication therapeutic mechanisms is that antidepressant medication reduces the density of 5-HT2A receptors (Carr and Lucki, 2011). 5-HT2A receptor levels are consistently reported to have increased in different brain regions of MDD patients, such as the hippocampus (Pandey et al, 2002) and the frontopolar cortex (Anisman et al, 2008) in human postmortem studies
Expression levels of HTR2A mRNA were increased in peripheral blood mononuclear cells of MDD, and mRNA levels of HTR2A itself were associated with depression severity (Amidfar et al, 2017)

Summary

Introduction

One of the common and sometimes fatal mental disorders is major depressive disorder (MDD), which is a leading cause of disability worldwide (Moussavi et al, 2007). Accumulating evidence from various studies such as adoption, family, and twin studies have shown that genetic factors play major roles in MDD development (Flint and Kendler, 2014; Shadrina et al, 2018). Many candidate genes gave hopeful preliminary results, which deserve further researching In these candidate genes, serotonin 2A receptor (HTR2A) gene is said to be correlated to susceptibility in MDD (Zhang et al, 1997; LacerdaPinheiro et al, 2014; Zhao et al, 2014). 5-HT2A receptor levels are consistently reported to have increased in different brain regions of MDD patients, such as the hippocampus (Pandey et al, 2002) and the frontopolar cortex (Anisman et al, 2008) in human postmortem studies. Expression levels of HTR2A mRNA were increased in peripheral blood mononuclear cells of MDD, and mRNA levels of HTR2A itself were associated with depression severity (Amidfar et al, 2017)

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