Research reportThe 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
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.
Section snippets
Subjects and clinical assessments
This study recruited a total of 401 patients with MDD (184 males and 217 females), aged 32.710 ± 11.061 years, and 391 age- and sex-matched control subjects, who did not have a history of neuropsychiatric disorders, in the period between March 2004 and February 2007. Both patients and control subjects came from the same geographically areas in the Northern China and they were all Chinese Han origin.
Clinical diagnosis was made by at least two consultant psychiatrists according to Diagnostic and
Results
The genotypic distributions of six polymorphisms were all in Hardy–Weinberg equilibrium in both the case group and the control group.
As shown in Table 2, allelic association was observed for the 5-HTTLPR (χ2 = 9.48, corrected P = 0.005, OR = 1.45) and rs6295 (χ2 = 5.56, corrected P = 0.016, OR = 0.76). The L-allele of 5-HTTLPR and the G-allele of rs6295 were more common in the patient group. The haplotype frequencies of the rs130058 and rs11568817 (D' = 0.98, r2 = 0117) in 5-HTR1B gene are shown in Table 3,
Discussion
In this study, all the patients were diagnosed as having MDD with the DSM-IV criteria and the semi-structured diagnostic interview tools were applied as well, although the self-report instrument for depression (less restrictive category) was commonly used in most studies of the gene–environment interaction (Caspi et al., 2003, Kaufman et al., 2004, Jokela et al., 2007, Eley et al., 2004). Our diagnostic approach seems to be more powerful than less restrictive depression in detection of the
Role of the funding source
This study was supported by the MOST (2006AA02A407, 2004CB518601 and 2006DFA31440), NSFC (30400263 and 30721063), and the Shanxi province (2007031091-3 and 2007021050). None of these funding bodies had any further role in study design; in the collection, analysis and interpretation of data; in the writing of the paper; or in the decision to submit the paper for publication.
Conflict of interest
No conflict of interest was involved in current work.
Acknowledgement
This study was supported by grants from the National 863 program (2006AA02A407), National 973 Program (2004CB518601), International S&T Cooperation Program of China (2006DFA31440), National Natural Science Foundation of China (30400263 & 30721063), Programs for Science and Technology Development of Shanxi (2007031091-3) and the Science Foundation for Youths of Shanxi (2007021050).
We thank the patients and families for their support and participation.
References (52)
- et al.
The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder
Biol. Psychiatry
(2005) - et al.
Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children
Biol. Psychiatry
(2006) - et al.
Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?
Biol. Psychiatry
(1998) The genetics of depression: a review
Biol. Psychiatry
(2006)- et al.
Polymorphism in serotonin transporter gene associated with susceptibility to major depression
Lancet
(1996) - et al.
Multifactor-dimensionality reduction reveals high-order interactions among estrogenmetabolism genes in sporadic breast cancer
Am. J. Med. Genet. B Neuropsychiatr. Genet.
(2001) - et al.
Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder
Biol. Psychiatry
(2006) - et al.
Developing novel treatments for mood disorders: accelerating discovery
Biol. Psychiatry
(2002) - et al.
Interactive effects of sex and 5-HTTLPR on mood and impulsivity during tryptophan depletion in healthy people
Biol. Psychiatry
(2007) Diagnostic and Statistical Manual of Mental Disorders
(2000)
The 5-HT(2A) receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients
Am. J. Med. Genet. B Neuropsychiatr. Genet.
Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT (1A) receptor gene as putative risk factors in major depression
Mol. Psychiatry
Evidence for a combined genetic effect of the 5-HT(1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram
J. Psychopharmacol.
Depressive disorders in Europe: prevalence figures from the ODIN study
Br. J. Psychiatry
The Camberwell Collaborative Depression Study. I. Depressed probands: adversity and the form of depression
Br. J. Psychiatry
Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene
Science
Cognitive impairment and social distress as different pathways to depression in the elderly: a cross-sectional study
Int. J. Geriatr. Psychiatry
The risk for depression conferred by stressful life events is modified by variation at the serotonin transporter 5HTTLPR genotype: evidence from the Spanish PREDICT-Gene cohort
Mol. Psychiatry
No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: results from two community surveys
Am. J. Med. Genet. B Neuropsychiatr. Genet.
A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans
J. Neurosci.
Gene–environment interaction analysis of serotonin system markers with adolescent depression
Mol. Psychiatry
Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders
Am. J. Med. Genet. B Neuropsychiatr. Genet.
The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression
Psychol. Med.
Allelic variation of human serotonin transporter gene expression
J. Neurochem.
Social relationships and health
Science
Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism
Neuropsychopharmacology
Cited by (82)
Dysregulation of miR-185, miR-193a, and miR-450a in the skin are linked to the depressive phenotype
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryInteraction effect between 5-HTTLPR and HTR1A rs6295 polymorphisms on the frontoparietal network
2017, NeuroscienceCitation Excerpt :These conflicting findings may be due to different subjects in different studies, such as cocaine users, healthy women, major depressive disorder patients, premenstrual dysphoric disorder patients, or more complicated mixed samples (Zilles et al., 2012; Weiss et al., 2014; Yen et al., 2014; Havranek et al., 2015; Wesnes et al., 2016), so it seems necessary to investigate the association of serotonin system with WM in a large healthy sample. Considering the strong neurobiological link between 5-HTT and 5-HT1A receptor (Li et al., 1999; Fabre et al., 2000; Li et al., 2000; Ase et al., 2001; Lundberg et al., 2007; Bose et al., 2011), we should examine the interaction of 5-HTTLPR and rs6295 on WM rather than the effect of a single polymorphism on WM. Recent studies indicate that the interaction between the 5-HTTLPR and HTR1A rs6295 polymorphisms is associated with psychiatric disorders and impaired decision-making (Arias et al., 2005; Zhang et al., 2009; Gu et al., 2013). However, no studies thus far have investigated the interaction of 5-HTTLPR with rs6295 in WM. Another reason for the inconsistent results may be the different neuropsychological tests used to evaluate WM performance.
Effects of bonding with parents and home culture on intercultural adaptations and the moderating role of genes
2017, Behavioural Brain ResearchCitation Excerpt :Some GxE studies on Asian have demonstrated effects opposite to what has been reported in Caucasian participants. For example, the effect of serotonin transporter gene polymorphisms on various psychological disorders are found to be in opposite directions among Caucasian and Asian populations (e.g., [103–106]. It is yet unclear why there might be divergent genetic effects between the ethnic groups.
Association between gene polymorphism and depression in Parkinson's disease: A case-control study
2017, Journal of the Neurological SciencesCitation Excerpt :Few studies have examined potential genetic risk factors for depression in PD. In the Chinese population, single-nucleotide polymorphisms (SNPs) at rs738499 in the Tef gene, rs78162420 in the TPH2 gene, rs1545843 in the SLC6A15 gene, and rs6295 in the 5HTR1A gene may be associated with depression [5–8]. These genes are involved in neurotransmitter biosynthesis, signaling, and metabolism.