Serotonin transporter candidate gene studies in affective disorders and personality: promises and potential pitfalls

Abstract

While affective and anxiety disorders are substantially heritable, their inheritances are complex and multifactorial. 1 It is therefore unsurprising that such etiologically heterogeneous illnesses have not easily succumbed to genetic methodologies that are further challenged by an imperfect classification system. 2 Nevertheless, investigators continue to behave as if the problems are not insoluble. Association studies of candidate genes have lately held particular appeal, at least partly since this approach connects well with the familiar view that these disorders arise from alterations in particular brain neurochemical systems.The evidence implicating brain serotonin (5-HT) neurotransmission in anxiety and affective disorders is extensive and compelling. 3,4 In the attempt to investigate whether alterations in function of brain 5-HT systems are etiologically associated with these illnesses, attention has focused on polymorphisms in genes encoding components of the serotonergic system. These genes are seen as potential candidates influencing susceptibility, course, or symptoms. Researchers are investigating variants of genes for the 5-HT synthesis pathway, the 5-HT transporter (5-HTT), and several of the numerous 5-HT receptors. Potentially important sequence variations may occur in the coding region of a gene, in gene promoters (which could affect transcription efficiency), and in intronic regions, which, while non-coding, might affect gene expression or distribution of the gene product. Some variants of serotonin system genes are common, consistent with a role in complex, polygenic disorders with relatively high population incidences.The most common research strategy used in association studies, because it is often logistically easiest, is the population-based approach. Such studies compare the frequencies of polymorphic alleles in a group of individuals with a particular psychiatric diagnosis with those in a reference population. The use of this method is now widespread. Although this strategy has important limitations (see below), initial findings have been intriguing enough to spur further research by diverse groups of investigators.A number of reports have described associations between affective disorders and polymorphisms in or near the 5-HTT gene. The 5-HTT is a major modulator

Platelet Serotonergic Markers as Endophenotypes for Obsessive-Compulsive Disorder

“…We did not observe an association between whole blood 5-HT level, K d , or B max of 5-HTT (measured with [ 3 H]-paroxetine and [ 3 H]-imipramine) and two polymorphismsin the 5-HTT gene, a 5-HTTLPR in the promoter region and a VNTRin intron 2, which act in vitro as transcriptional regulators (Lesch et al, 1996;McKenzie and Quinn, 1999). The lack of association between 5-HT levels and 5-HTT polymorphisms is in accordance with previous reports in individuals suffering from autism (Betancur et al, 2002), alcoholism (Stoltenberg et al, 2002), or in healthy subjects (Greenberg et al, 1998). However, the possibility that other polymorphisms within regulatory or coding sequences at the 5-HTT locus could be more directly linked to the low blood 5-HT level observed in OCD patients cannot be excluded.…”

A Large Case–Control Study of Common Functional SLC6A4 and BDNF Variants in Obsessive–Compulsive Disorder

“…In addition to these titration experiments, we confirmed that all of our genotyped biallelic markers were in HWE. This test is frequently employed to screen for genotyping errors, and although it is neither overly sensitive nor powerful (Leal, 2005), deviation from HWE has been observed in several 5-HTTLPR genotyping studies (Greenberg et al, 1998;Munafo et al, 2005;Yonan et al, 2006). That being said, lack of deviation from HWE does not rule out genotyping errors, and the MgCl 2 -dependent preferential amplification discussed above emphasizes the necessity to validate genotyping assays in future analyses of SLC6A4 5-HTTLPR, STin2, and other size-polymorphic loci.…”

A meta-analysis of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety

“…These studies have produced a large set of both positive and negative results and have generated extensive comment about the strength of the relationship and the methodological conditions under which the relationship hold. [5][6][7][8] To date, however, no formal statistical analysis has addressed the collection of studies examining the relationship between 5-HTTLPR and trait anxiety. In this study, we conducted meta-analyses of existing studies to provide formal statistical measures of the strength of this relationship.…”