Mixture regression analysis on age at onset in Bipolar Disorder patients: Investigation of the role of serotonergic genes

Bipolar Disorder (BPD) is a complex psychiatric disease with a relevant underlying genetic basis. HTR2A T102C, HTR2C Cys23Ser, SLC6A4 5-HTTLPR and rs25531 polymorphisms were genotyped in 230 BPD patients and inserted as covariates in a mixture regression model of age at onset (AAO). 5-HTTLPR polymorphism associated with early onset component under recessive and additive model. HTR2A T102C, HTR2C Cys23Ser and 5-HTTLPR interaction terms associated with early onset component under dominant, recessive and additive model. These findings suggest a role of genes codifying for elements of the serotonergic system in influencing the AAO in BPD.     

Obsessive-compulsive disorder and the promoter region polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4): a negative association study in the Afrikaner population

A polymorphism (5-HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) has been reported to have functional significance and to be associated with obsessive-compulsive disorder (OCD). However, other studies have generated confounding results. A study was undertaken to re-evaluate this association in subjects drawn from the relatively genetically homogeneous Afrikaner population of South Africa. Fifty-four OCD patients of Afrikaner descent and 82 ethnically matched control individuals were phenotyped and genotyped. No significant association was found between the distribution of the 5-HTTLPR genotypes at the SLC6A4 locus and OCD. A similar result (p = 0.108) was generated when a meta-analysis of the 5-HTTLPR polymorphism, combining the current study with a previously reported Caucasian group, was performed; the meta-study comprised 129 OCD patients and 479 control individuals. However, both studies lacked power. Therefore, evidence that variation in SLC6A4 plays a significant role in the development of OCD in the population groups studied is inconclusive. Future association studies in Caucasian populations may extend the power of such meta-analyses and assist in delineating the role of SLC6A4 in OCD.     

Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers

Background

Pharmacologic studies implicate a significant role of genes encoding the serotonin transporter (SLC6A4) and the 5-HT_3AB subunits HTR3A and HTR3B in nicotine dependence (ND). However, whether they are involved in ND remains largely unknown.

Methods

Here, we examined the impact of variations in the three genes on ND in 1366 individuals from 402 African American (AA) and 671 individuals from 200 European American (EA) families. The ND of each smoker was assessed with smoking quantity (SQ), heaviness of smoking index (HSI), and Fagerström test for nicotine dependence (FTND).

Results

Association analysis revealed marginal association of rs10160548 in HTR3A with SQ and HSI in AA, 5-HTTLPR in SLC6A4 with FTND in EA, and rs11606194 in HTR3B with SQ and FTND in the pooled sample. Haplotype-based association analysis revealed a few major haplotypes in HTR3A that were significantly associated with ND in the AA, EA, and pooled samples. However, none of these associations remained significant after correcting for multiple testing except for a haplotype G-C-C-T-A-T formed by SNPs rs1150226, rs1062613, rs33940208, rs1985242, rs2276302, and rs10160548 in HTR3A for the AA sample. Considering biological functions of the three genes, we examined interactive effects of variants in the three genes, which revealed significant interactions among rs1062613 and rs10160548 in HTR3A, rs1176744 in HTR3B, and 5-HTTLPR and rs1042173 in SLC6A4 in affecting ND in the three samples.

Conclusions

We conclude that SLC6A4, HTR3A and HTR3B play a significant role in ND through genetic interactions.     

Association study between BDNF gene variants and Mexican patients with obsessive–compulsive disorder

Obsessive–compulsive disorder (OCD) is a psychiatric disorder whose etiology is not yet known. We investigate the role of three variants of the BDNF gene (rs6265, rs1519480 and rs7124442) by single SNP and haplotype analysis in OCD Mexican patients using a case–control and family-based association design. BDNF gene variants were genotyped in 283 control subjects, 232 OCD patients and first degree relatives of 111 OCD subjects. Single SNP analysis in case–control study showed an association between rs6265 and OCD with a high frequency of Val/Val genotype and Val allele (p=0.0001 and p=0.0001, respectively). Also, genotype and allele analysis of rs1519480 showed significant differences (p=0.0001, p=0.0001; respectively) between OCD and control groups. Haplotype analysis showed a high frequency of A–T (rs6265–rs1519480) in OCD patients compared with the control group (OR=2.06 [1.18–3.59], p=0.0093) and a low frequency of haplotype A–C in the OCD patients (OR=0.04 [0.01–0.16], p=0.000002). The family-based association study showed no significant differences in the transmission of any variant. Our study replicated the association between BDNF Val66Met gene polymorphism and OCD. Also, we found a significant association of rs1519480 in OCD patients compared with a control group, region that has never been analyzed in OCD. In conclusion, our findings suggest that BDNF gene could be related to the development of OCD.     

BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met × 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.     

Gender moderates the association between 5-HTTLPR and decision-making under ambiguity but not under risk

Decisions made under ambiguity may involve a different genetic architecture than those made under risk. Because gender moderates the effect of genetic polymorphisms on serotonin function and because there are gender differences in decision-making, the present study examined potential gender moderation of associations between polymorphisms in important serotonin system candidate genes (serotonin transporter [SLC6A4] and tryptophan hydroxylase-2 [TPH2]) and performance on a decision-making task (Iowa Gambling Task, IGT) in healthy, adults (N = 188; 62% women). Subjects were genotyped for the well-studied SLC6A4 promoter variant 5-HTTLPR and a TPH2 single nucleotide polymorphism in intron-8 (rs1386438). Genotype at rs1386438 was not associated with performance on the IGT. A significant gender by 5-HTTLPR genotype interaction effect was detected when decision-making was under ambiguity (i.e. the first block of 20 choices), but not under risk (blocks 2-5). Performance on the first block of 20 choices was not correlated with performance on subsequent blocks, supporting the interpretation that early performance on the IGT indexes decision-making under ambiguity, while performance on blocks 2-5 indexes decision-making under risk. These findings suggest that decision-making under ambiguity and risk may have different genetic architectures and that individual differences in decision-making under ambiguity are associated with genetic variation in SLC6A4.     

Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits.

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus--in interaction with other gene variants--influences anxiety- and depression-related personality traits.     

Association study of the serotonin transporter gene polymorphism in obsessive-compulsive disorder

The hypothesis implicating the serotonergic system in the pathophysiology of obsessive-compulsive disorder (OCD) is supported by the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRIs). Since SSRIs act on the serotonin transporter (5-HTT), it has been suggested that the 5-HTT gene (SCL6A4) could be a good candidate for OCD. The SCL6A4 gene has a 44-bp insertion/deletion polymorphism in its promoter region (5-HTTLPR). Previous studies have revealed an association between OCD and the l allele. We analysed the 5-HTTLPR polymorphic system in 115 Mexican OCD patients and 136 controls. No significant association was found between l allele and OCD (chi2 = 1.54, d.f. = 1, p = 0.21). Furthermore, we assessed alternative methods that employ family-based designs in a sample of 43 trios. Haplotype-based haplotype relative risk and transmission disequilibrium analysis did not show a preferential transmission of l allele to OCD probands. Our results indicate the need to analyse larger samples using family-based methods.     

Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS

The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs [rs2097603; rs4680 (158Val/Met); rs165599] representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, chi2=4.38, p=0.036) and OCD (OR 4.00, chi2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population.     

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1 ± 11.6 years, 68% females) treated with escitalopram 10–20 mg/day for 12 weeks. There were no significant associations between 5-HTT promoter region polymorphisms and response rate or mean change of depressive symptoms during escitalopram treatment. However we showed that patients carrying S allele of 5-HTTLPR may have increased risk for some side effects, including headache, induced by escitalopram medication.     

Serotonin transporter-linked polymorphic region (5-HTTLPR) genotype is associated with cortisol responsivity to naloxone challenge

Rationale

The serotonergic and opioidergic neurotransmitter systems are critical regulators of the hypothalamic?Cpituitary?Cadrenal (HPA) axis through their respective excitatory and inhibitory inputs. Serotonin transporter (5-HTT) genotype has been studied as a marker of HPA axis dysregulation and for predicting risk of psychopathology, with mixed findings.

Objectives

We stimulated the HPA axis with naloxone, an opioid receptor antagonist, to examine cortisol reactivity based on 5-HTT-linked polymorphic region (5-HTTLPR) genotypes.

Methods

Healthy community volunteers (N?=?78) received intravenous (IV) placebo followed by sequential doses of IV naloxone (50, 100, 200, and 400???g/kg) every 30?min. Plasma cortisol was measured every 15?min. Participants were genotyped for the long (L) and short (S) alleles of the 5-HTT gene and for rs25531 (A/G) in the 5-HTTLPR repetitive element and compared by the 5-HTTLPR/rs25531 genotype (triallele) and by the 5-HTTLPR genotype (biallele) classification.

Results

In triallele analyses, individuals with one or more L _A alleles showed higher cortisol response to naloxone compared with individuals with no L _A alleles. In biallele analyses, less robust effects were found, although individuals with two L alleles showed a higher cortisol response compared with other genotypes.

Conclusions

Naloxone blockade leads to a greater activation of the HPA axis among individuals with the L _A allele. Including rs25531 in the analysis with the 5-HTTLPR genotype appears more sensitive in detecting genetic differences in naloxone-induced cortisol than when using only the 5-HTTLPR genotype. Future research should investigate the interactive effects between the serotonergic and opioidergic systems on HPA axis dysregulation and psychopathophysiology.     

The HTR1A and HTR1B receptor genes influence stress-related information processing

The serotonergic system has been widely implicated in stress related psychiatric disorders such as depression and anxiety. We investigated the possible association between depression and anxiety scores and SNPs within the HTR1A and HTR1B genes in a population sample (n = 1387). There was no direct SNP-phenotype association, but in interaction with recent stressful life events rs6295 G, rs878567 T alleles and rs6296 C alleles were associated with significantly higher symptom scores. A subset of control subjects (n = 101) took part in a computerised face emotion processing task. Healthy rs6295 GG carriers did not show an affective bias to perceive more negative emotions but reacted more quickly to fearful faces. Thus we conclude that the serotonin-1A receptor conveys vulnerability to these psychiatric disorders by modulating threat-related information processing. Our results extend previous findings of an interaction between stressful life events and the serotonin transporter gene to two other genes in the serotonergic pathway and emphasise the possible role of increased threat-related information processing as an intermediate phenotype.     

Genetics and Epigenetics in Major Psychiatric Disorders

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.     

Human genetics and pharmacology of neurotransmitter transporters

Biogenic amine neurotransmitters are released from nerve terminals and activate pre- and postsynaptic receptors. Released neurotransmitters are sequestered by transporters into presynaptic neurons, a major mode of their inactivation in the brain. Genetic studies of human biogenic amine transporter genes, including the dopamine transporter (hDAT; SLC6A3), the serotonin transporter (hSERT; SLC6A4), and the norepinephrine transporter (hNET; SLC6A2) have provided insight into how genomic variations in these transporter genes influence pharmacology and brain physiology. Genetic variants can influence transporter function by various mechanisms, including substrate affinities, transport velocity, transporter expression levels (density), extracellular membrane expression, trafficking and turnover, and neurotransmitter release. It is increasingly apparent that genetic variants of monoamine transporters also contribute to individual differences in behavior and neuropsychiatric disorders. This chapter summarizes current knowledge of transporters with a focus on genomic variations, expression variations, pharmacology of protein variants, and known association with human diseases.     

5-HT1A gene variants and psychiatric disorders: a review of current literature and selection of SNPs for future studies

5-HT1A receptors are key components of the serotonin system, acting both pre- and post- synaptically in different brain areas. There is a growing amount of evidence showing the importance of 5-HT1A in different psychiatric disorders, from mood to anxiety disorders, moving through suicidal behaviour and psychotic disorders. Findings in the literature are not consistent with any definite 5-HT1A influence in psychiatric disorders. 5-HT1A gene variants have been reported to play some role in mood disorders, anxiety disorders and psychotic disorders. Again, the literature findings are not unequivocal. Concerning response to treatment, the C(-1019)G variant seems to be of primary interest in antidepressant response: C allele carriers generally show a better response to treatment, especially in Caucasian samples. Together with the C(-1019)G (rs6295) variant, the Ile28Val (rs1799921), Arg219Leu (rs1800044) and Gly22Ser (rs1799920) variants have been investigated in possible associations with psychiatric disorders, also with no definitive results. This lack of consistency can be also due to an incomplete gene investigation. To make progress on this point, a list of validated single nucleotide polymorphisms (SNPs) covering the whole gene is proposed for further investigations.     

Serum uric acid levels are associated with polymorphisms in the SLC2A9, SF1, and GCKR genes in a Chinese population

Aim:

Genome-wide association studies have identified several novel loci associated with serum uric acid concentrations in individuals of European descent. In the current study, we aimed to evaluate the associations between these loci and serum uric acid concentrations in a Chinese population.

Methods:

Fourteen single nucleotide polymorphisms (SNPs) mapped in or near 11 loci (PDZK1, GCKR, LRP2, SLC2A9, ABCG2, LRRC16A, SLC17A1, SLC17A3, SLC22A11, SLC22A12 and SF1) were genotyped in 2329 Chinese subjects in Shanghai. Serum biochemical parameters including uric acid concentrations were determined. All the variants were analyzed for gender differences since uric acid metabolism differed between genders.

Results

In males after adjustments for age and BMI, GCKR rs780094, SLC2A9 rs11722228 and SF1 rs606458 were associated with the uric acid concentrations, which were statistically significant (P=0.016, 0.001 and 0.03, respectively), whereas SLC2A9 rs3775948 was marginally associated with the uric acid concentrations (P=0.071). In females, SLC22A12 rs506338 was also marginally associated with the uric acid concentrations (P=0.057). The meta-analysis for combined data from both males and females revealed that rs3775948 and rs606458 were associated with the uric acid concentrations (P=0.036 and 0.043, respectively). Furthermore, the gender significantly affected the association of rs11722228 with serum uric acid levels (P=0.012).

Conclusion

The SLC2A9 rs11722228, SF1 rs606458 and GCKR rs780094 variants modulate uric acid concentrations in Chinese males, while SF1 rs606458 and SLC2A9 rs3775948 are associated with the uric acid concentrations in both Chinese males and females.     

A high density linkage disequilibrium mapping in 14 noradrenergic genes: evidence of association between SLC6A2, ADRA1B and ADHD

Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder (ADHD). Until recently, the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates. In this study, 91 SNP markers of 14 noradrenergic genes (an average density of one SNP per 4.5 kbp) were examined in ADHD samples from Ireland and Australia. Although suggestive evidence of association (nominal p?≤?0.05) with the genes SLC6A2, ADRA1A, ADRA1B and ADRA2B was observed, none remained significant after permutation adjustments. In contrast, haplotype analyses demonstrated a significant association between ADHD and a SLC6A2 haplotype comprising the markers rs36009, rs1800887, rs8049681, rs2242447 and rs9930182 (χ²?=?9.39, p-corrected?=?0.019, OR?=?1.51). A rare ADRA1B haplotype made of six SNPs (rs2030373, rs6884105, rs756275, rs6892282, rs6888306 and rs13162302) was also associated (χ²?=?7.79, p-corrected?=?0.042 OR?=?2.74) with the disorder. These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD. The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions. Functional genomic analysis is warranted to determine the biological mechanism of the observed association.     

Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders.

Anxiety sensitivity (AS) is a dispositional characteristic that predisposes to the development of anxiety disorders (eg, panic and post-traumatic stress disorder) and major depression. AS is subject to genetic and environmental influences, the former as yet unidentified and the latter known to include childhood maltreatment. The serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) has been associated with depression, but most consistently in the context of environmental stress. We tested the hypothesis that 5-HTTLPR genotype and childhood maltreatment would interact to increase susceptibility to AS in young adults. Subjects were European-American college undergraduates (N=150, median age 18 years) characterized on a measures of AS (Anxiety Sensitivity Index) and retrospective childhood maltreatment (Childhood Trauma Questionnaire [CTQ]). 5-HTTLPR genotypes were obtained from blood-derived DNA. Linear regression was used to model relationships between 5-HTTLPR, childhood emotional abuse, and AS; covariates such as sex, neuroticism, and ancestral proportion scores were incorporated into some models in a larger, ethnically heterogenous sample (N=247) to evaluate robustness of the findings to model assumptions. A statistically signficant interaction was observed between levels of childhood emotional (or physical) maltreatment and 5-HTTLPR genotype. Specifically, S/S individuals with higher levels of maltreatment had significantly higher levels of AS than subjects in other groups. No such relationship was found for neuroticism, attesting to the possible specificity of the findings for AS. Findings were consistently robust to the inclusion of covariates, and were not confounded by population stratification. In conclusion, these results provide evidence of a specific genetic influence on anxiety sensitivity-an intermediate phenotype for anxiety (and depressive) disorders; this effect is modified by severity of childhood maltreatment. These findings are consistent with the notion that 5-HTTLPR operates broadly to moderate emotional responsivity to stress.     

Serotonergic genes and suicide: A systematic review

Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5-HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene–environment interactions.     

Human serotonin transporter gene (SLC6A4) variants: their contributions to understanding pharmacogenomic and other functional G×G and G×E differences in health and disease

Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5', 3' UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiological changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metabolism. Polymorphisms in SLC6A4 are associated with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene×gene (G×G) and gene×environment (G×E) interactions nonetheless remains incompletely understood, with some association findings remaining controversial. Considering its primary importance in the regulation and function of the entire serotonergic system (as evidenced by the consequences of SERT-mediated reuptake inhibition by SRIs like fluoxetine in humans and of genetically engineered changes in mice and rats), it seems likely that SLC6A4 and SERT will remain areas of high interest in our field's attempts to better understand and treat 5-HT-related disorders.