The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population

Abstract

Background

Serotonin transporter (5-HTT) and 5-HT receptor (5-HTR) involved in the neurotransmission of 5-HT may play an important role in the development of major depression disorder (MDD). Several lines of evidence suggested that the gene–environment interaction may confer susceptibility to depression. The aim of this study is to analyze the combined effect of four serotonin-related genes and two environmental factors on MDD in a Chinese population.

Methods

This study recruited a total of 401 patients with MDD and 391 age- and gender-matched control subjects. They were all Chinese Han origin. Negative life events and objective social supports were assessed using standard rating scales. Six polymorphisms in the four serotonin-related genes (5-HTT, 5-HTR1A, 5-HTR1B and 5-HTR2A) were selected to detect. The analyses of the gene–environment interactions were performed by the Multifactor Dimensionality Reduction (MDR).

Results

Allelic associations between patients with MDD and controls were observed for the polymorphism of 5-HTTLPR and for rs6295 at the 5-HTR1A locus. The 5-HTTLPR polymorphism was associated with negative life events on MDD. A three-way interaction between the 5-HTTLPR polymorphism, rs6295 and negative life events on MDD was found in the individuals aged from 20 years to 29 years. In addition, the individuals carrying the L/L genotype of 5-HTTLPR could be susceptible to MDD when exposed to negative life events.

Conclusions

The 5-HTTLPR polymorphism may modify the interaction between negative life events and MDD in the Chinese population. To our knowledge, this is the first report on the combined effect for the 5-HTTLPR polymorphism and 5-HTR1A genes on modifying the response to negative life events conferring susceptibility to MDD in the 20–29 year group.

Introduction

Major depressive disorder (MDD) is one of the most common and severe mental disorders. It is clinically characterised with cognitive impairments, functional disability and mortality, and affects 7%–11% of the general population (Ayuso-Mateos et al., 2001, Kessler et al., 2007). A number of studies suggest that MDD may be a typical complex disease involving both genetic and environmental factors (Kendler et al., 2002, Levinson, 2006).

Serotonin (5-HT) is an important neurotransmitter involved in regulating a number of physiological activities, such as emotion, cognition, circadian and rhythms. Several lines of evidence indicate that the functional impairment of the 5-HT system plays a significant role in the pathogenesis of depression (Lesch and Mössner, 1998, Schloss and Williams, 1998, Tamminga et al., 2002). Studies of candidate genes show that the genetic polymorphisms of the 5-HT system are very likely to contribute to the development of MDD. The following genes have been investigated by most studies of the relationship between the genetic polymorphisms of the 5-HT system and MDD. These genes include those coding for 5-HT transporter (5-HTT), HTR1A, HTR1B and HTR2A.

The 5-HTT gene, also called SLC6A4, is the first locus studied for genetic association with MDD. It is mapped to chromosome 17q11.1–17q12 and contains 14 exons (Ramamoorthy et al., 1993). There are two functional polymorphisms at the 5-HTT locus: the 44-bp insertion-deletion polymorphism in the promoter region (5-HTTLPR)(Heils et al., 1996) and the variable number tandem repeat(VNTR) in intron 2 (STin2) (Ogilvie et al., 1996). A few studies suggest that the short allele (S-allele) of 5-HTTLPR and allele 12 of STin2 may confer genetic risk for depression (Liu et al., 1999, Serretti et al., 2002, Hoefgen et al., 2005). Moreover, the polymorphisms of several receptor genes regarding the 5-HT system have also been investigated as a genetic component for depression. For example, single neucletide polymorphisms(SNPs) , including rs6295 (− 1019C/G base change) in the 5-HT receptor 1A (5-HTR1A) locus, rs130058 and rs11568817 in the 5-HT receptor 1B(5-HTR1B) locus and rs6313(102C/T) in the 5-HT receptor 2A (5-HTR2A) locus, have been reported to be associated with depression, bipolar disorder and suicide attempt (Arias et al., 2001, Huang et al., 2003, Lemonde et al., 2003). However, the findings reported to date were not conclusive due to poor replication (Kato, 2007).

In addition to research into the possible genes for depression and related diseases, etiological contributions of some environmental factors to depression should be taken into account. Some studies suggest that negative life events may be a major environmental factor for the risk of depression (Cervilla and Prince, 1997, Bebbington et al., 1988) as social support can reduce the risk of depression triggered by stressful life events (House et al., 1988). It means that social support may be an important protective factor of individuals from depression (Kaufman et al., 2004). To further understand the pathogenesis of depression, it is necessary to study the gene–environment interaction that plays a crucial role in developing the illness. Recent studies have reported on some interesting findings on the interaction between the genes functioning in the 5-HT system and environmental contributions to the risk for depression or its symptoms (Caspi et al., 2003, Kaufman et al., 2004, Kendler et al., 2005, Kim-Cohen et al., 2006, Jacobs et al., 2006, Walderhaug et al., 2007). The S-allele of 5-HTTLPR has been found to be associated with depression only in the individuals with a history of childhood maltreatment or recent stressful life events (Caspi et al., 2003, Kaufman et al., 2004, Eley et al., 2004, Cervilla et al., 2007), although some studies failed to replicate such a gene–environment interaction in depression (Gillespie et al., 2005, Surtees et al., 2006, Chipman et al., 2007). Jokela et al. (2007) suggest that rs6313 in the 5-HTR2A gene can interact to maternal nurturance in childhood and consequently develop depressive symptoms in late life. Social support seems to be important in protecting individuals from pathological effects of the 5-HTTLPR and negative life events on depression (Kaufman et al., 2004, Kaufman et al., 2006).Accordingly, the present study was designed to examine the relationship among six functional polymorphisms in the four serotonin-related genes as mentioned above, negative recent life events, objective social supports and MDD in a Chinese population.