The serotonin transporter in Alzheimer's and Parkinson's disease

The etiology of late-onset Alzheimer's disease (AD) and idiopathic Parkinson's disease (PD) is not known. In both disorders there is an extensive degeneration of serotonergic neurons, with corresponding losses of the serotonin (5HT) transporter (5HTT), which is responsible for the reuptake of 5HT from the synaptic cleft. An increasing body of evidence indicates that allelic variation of the 5HTT gene promoter (5HTT gene-linked polymorphic region, 5HTTLPR) determines high or low 5HT uptake in normal human brain. Association studies show that the low-activity allele of the 5HTTLPR is a risk factor for late-onset AD. In PD, the 5HTTLPR influences the risk of developing depression, a common symptom in PD patients. A compromised serotonergic system thus plays an important role in the pathophysiology of both AD and PD.     

Serotonin transporter polymorphisms and measures of impulsivity,aggression, and sensation seeking among African-American cocaine-dependent individuals

Considerable evidence indicates that serotonergic mechanisms, particularly the serotonin transporter (5HTT), may mediate central effects of cocaine and may also be involved in impulsive and aggressive behavior. We investigated whether polymorphisms in the 5HTT gene were related to traits of impulsivity, sensation seeking, and aggression among cocaine abusers. Standardized measures of these personality traits were obtained in a sample of 105 severely affected cocaine-dependent African-American subjects and 44 African-American controls. Two polymorphisms of the 5HTT gene were examined involving the 5' promoter (5HTTLPR) region and a 17 base pair variable-number-tandem-repeat (VNTR) marker among cocaine patients. No significant relationships were observed between polymorphic variants of the 5HTTLPR and VNTR regions and scores on any of the trait measures. Similarly, demographic variables and measures of severity of substance use and depression were unrelated to allele frequencies or genotype distributions of the variants among cocaine patients. As expected, cocaine patients scored significantly higher on total scores of impulsivity, aggression, and sensation seeking compared to controls. The findings do not seem to support an association between these polymorphisms in the 5HTT gene and impulsive-aggressive traits among cocaine-dependent African-American individuals.     

Gene-environment interaction analysis of serotonin system markers with adolescent depression

We report analyses from a study of gene-environment interaction in adolescent depression. The sample was selected from 1990 adolescents aged 10-20 years: those with depression symptoms in the top or bottom 15% were identified and divided into high or low environmental risk groups. DNA was obtained from 377 adolescents, representing the four quadrants of high or low depression and high or low environmental risk. Markers within, or close to, each of the serotonergic genes 5HTT, HTR2A, HTR2C, MAOA (monoamine oxidase type A) and tryptophan hydroxylase (TPH) were genotyped. Environmental risk group was a nonsignificant predictor and sex was a significant predictor of the depression group. HTR2A and TPH significantly predicted the depression group, independent of the effects of sex, environmental risk group and their interaction. In addition, there was a trend for an effect of 5HTTLPR, which was significant in female subjects. Furthermore, there was a significant genotype-environmental risk interaction for 5HTTLPR in female subjects only, with the effect being in the same direction as another recent study, reaffirming that an important source of genetic heterogeneity is exposure to environmental risk.     

Depression and anxiety in Parkinson's disease: possible effect of genetic variation in the serotonin transporter.

Recently, a functional polymorphism in the promoter region of the serotonin transporter gene has been linked to anxiety. In cell culture, the short allele of this polymorphism synthesizes less serotonin transporter, resulting in a reduction of the removal of serotonin from the synaptic cleft. This pilot study examines depression and anxiety in Parkinson's disease patients as a function of the variation in this polymorphism. Thirty-two patients were genotyped and then blindly administered the Hamilton Depression and Anxiety Scales. Clinical data on the neurologic features of the disease were also gathered. Patients with the short allele of the serotonin transporter promotor scored significantly higher on both the depression and anxiety measures. There were no differences between groups for any neurologic variable. Patients with the short allele were more likely to have scores for anxiety and depression that indicated "caseness." This study suggests that the short allele of the serotonin transporter gene may represent a significant risk factor for the development of anxiety and depression in Parkinson's disease patients.     

Serotonin polymorphisms and posttraumatic stress disorder in a trauma exposed African American population

Background : Genetic polymorphisms that influence serotonin (5‐hydroxytryptamine, 5HT) neurotransmission are candidates for contributing to susceptibility to posttraumatic stress disorder (PTSD). The objective of our study was to determine if a variable length polymorphism for the promoter regions of the 5HT transporter (5HTTLPR), and/or a substitution polymorphism in the promoter region for the 5HT2A receptor, would be associated with PTSD in a trauma exposed population of adult African‐Americans. Methods : Using a case control design, 118 participants recruited from the primary care clinics and the campus of a historically black university who met inclusion criteria including trauma exposure provided blood samples for genomic DNA. PTSD criteria were determined by the Clinician Assessment of PTSD Scale (CAPS) and criteria for other psychiatric disorders by the Structured Clinical Interview for DSM‐IV (SCID). 5HTTLPR and 5HT2A‐1438A/G were genotyped using established methods. Associations of genotypes with lifetime PTSD, and models testing associations of allele “dose”, were analyzed. Results : Fifty‐five (47%) participants met lifetime criteria for PTSD and 26 (22%) met criteria for (mostly comorbid) major depression. The 5HT2A (lower expressing) G allele was significantly associated with PTSD. We did not find significant associations with 5HTTLPR. Conclusions : Our findings suggest a relationship between genetic variation in the 5HT2A promoter region and PTSD. Depression and Anxiety 26:993–997, 2009. Published 2009 Wiley‐Liss, Inc.     

Interaction of chronic stress with serotonin transporter and catechol‐O‐methyltransferase polymorphisms in predicting youth depression

Background: Investigations of gene–environment interaction (G×E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5‐HTTLPR) as a moderator of the stress–depression relationship. However, recent evidence for 5‐HTTLPR G×E in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol‐O‐methyltransferase (COMT) gene on the strength of 5‐HTTLPR G×E. Methods: A community sample of youth ( n =384) was genotyped for 5‐HTTLPR and COMT. A multi‐method, multi‐informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G×G×E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results: Significant three‐way interactions were observed for both depressive symptoms and diagnoses, such that 5‐HTTLPR G×E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5‐HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two‐way G×E was found for 5‐HTTLPR. Conclusions: Inconsistent 5‐HTTLPR G×E findings to date may be partly attributable to unmeasured epistatic effects between 5‐HTTLPR and COMT val158met. Identifying the conditions under which 5‐HTTLPR G×E is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

DJ-1基因启动子区g.168_185del的多态性与帕金森病的关系

目的 了解DJ-1基因启动子区g.168_185del的多态性与帕金森病(PD)的关系.方法 采用病例-对照研究,应用聚合酶链反应、DNA测序等技术,对湖南汉族213例PD患者和195名正常对照者的DJ-1基因g.168_185del多态性进行检测.结果 g.168_185del多态在各组的基因型频率和等位基因频率比较差异无统计学意义(均P>0.05).结论 g.168_185del多态位点不是本组PD患者的患病危险因素.     

Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives.     

Reported childhood abuse is associated with low serotonin transporter binding in vivo in major depressive disorder

Background: Physical or psychological adversity in childhood is associated with a higher risk for depression in adulthood, and with persistent serotonergic abnormalities in humans and in animal models. We hypothesized that reported childhood abuse would be associated with lower brain serotonin transporter (5‐HTT) binding potential (BP_P, proportional to the number of available transporters) in adults. We examined healthy volunteers and subjects with major depressive disorder, a sample enriched for childhood abuse. Methods: Regional brain 5‐HTT BP_P was measured using positron emission tomography (PET) with [¹¹C]McN 5652 and a metabolite‐corrected arterial input function in 43 healthy volunteers and 23 subjects in a major depressive episode, ten of whom reported a history of sexual and/or physical abuse before age 15, and 13 of whom did not. As only two healthy volunteers reported childhood abuse, primary analyses were restricted to the depressed sample, with healthy controls presented as comparators. Results: Depressed subjects reporting childhood abuse had lower 5‐HTT BP_P than nonabused depressed subjects across all brain regions examined (P = 0.017). The groups did not differ in relevant demographic or clinical variables. Genotype frequencies of a functional polymorphism in the 5‐HTT gene promoter (5‐HTTLPR) did not differ between the groups. Conclusions : Reported childhood abuse is associated with lower 5‐HTT BP_P in this sample of subjects with major depression, consistent with other reports that childhood adversity can lower serotonergic function permanently. Lower 5‐HTT BP_P may represent a biological pathway through which early life stress predisposes to the development of subsequent psychiatric illness, including major depressive disorder. Synapse 63:565–573, 2009. © 2009 Wiley‐Liss, Inc.     

Oestradiol Alters Central 5‐HT1A Receptor Binding Potential Differences Related to Psychosocial Stress but not Differences Related to 5‐HTTLPR Genotype in Female Rhesus Monkeys

Social subordination in female macaques represents a well‐described model of chronic psychosocial stress. Additionally, a length polymorphism (5‐HTTLPR) in the regulatory region of the serotonin (5‐HT) transporter (5‐HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to that described in humans with an analogous 5‐HTTLPR polymorphism. The present study determined the effects of social status and the 5‐HTTLPR genotype on 5‐HT1A receptor binding potential (5‐HT1A BP_ND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β‐oestradiol (E₂) treatment. Areas analysed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography using p‐[¹⁸F]MPPF was performed to determine the levels of 5‐HT1A BP_ND under a non‐E₂ and a 3‐week E₂ treatment condition. The short variant (s‐variant) 5‐HTTLPR genotype produced a significant reduction in 5‐HT1A BP_ND in the mPFC regardless of social status, and subordinate s‐variant females showed a reduction in 5‐HT1A BP_ND within the ACC. Both these effects of 5‐HTTLPR were unaffected by E₂. Additionally, E₂ reduced 5‐HT1A BP_ND in the dorsal raphe of all females irrespective of psychosocial stress or 5‐HTTLPR genotype. Hippocampal 5‐HT1A BP_ND was attenuated in subordinate females regardless of 5‐HTTLPR genotype during the non‐E₂ condition, an effect that was normalised with E₂. Similarly, 5‐HT1A BP_ND in the hypothalamus was significantly lower in subordinate females regardless of 5‐HTTLPR genotype, an effect reversed with E₂. Taken together, the data indicate that the effect of E₂ on modulation of central 5HT1A BP_ND may only occur in brain regions that show no 5‐HTTLPR genotype‐linked control of 5‐HT1A binding.     

Family-based association test of the 5HTTLPR and aggressive behavior in a general population sample of children.

BACKGROUND: A promoter polymorphism in the serotonin transporter (5HTTLPR) has functional effects on an important physiologic process involved in serotonin (5HT) signaling. Despite the fact that variation in the 5HT system has long been implicated in the etiology of aggressive behaviors, only a few association-based studies with mixed results have been reported. METHODS: We conducted family-based tests of association in a sample of 366 families from which 1187 genotypes of the 5HTTLPR were generated using polymerase chain reaction. Ratings of aggressive behavior were obtained from parents and teachers longitudinally using the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF), instruments widely used in behavioral and psychiatric genetics. RESULTS: Within-family tests suggest an association between the s-allele of the 5HTTLPR and higher aggressive behavior in middle childhood. The strongest association was at age 9 and for an aggregate measure of teacher-rated aggressive behavior. CONCLUSIONS: This is the first report of an association analysis of the 5HTTLPR in a general population sample of school-age children. The results provide some support for the hypothesis that the functional effects of the 5HTTLPR s-allele are associated with higher levels of aggressive behavior in middle childhood.     

Associations of the serotonin transporter promoter polymorphism with aggressivity,attention deficit,and conduct disorder in an adoptee population

Prior studies of the Iowa Adoption cohorts have demonstrated that the degree of adoptee aggressiveness and conduct disorder has a significant genetic component. Other studies have implicated the neurotransmitter serotonin or polymorphisms in the serotonin transporter gene (5HTT) as an important source of variability in "externalizing" behaviors such as aggressivity, conduct disorder, and attention deficit-hyperactivity disorders (ADHD). Following this lead, we genotyped a subgroup of adoptees (n = 87) at high risk for these kinds of disorders with respect to the serotonin-transporter-linked promoter region (5HTTLPR) polymorphism, and used ordinal logistic regression to conduct an association study. Primary analysis failed to detect a main effect between 5HTTLPR status and subscales of aggressivity, conduct disorder, or attention deficit. However, when biologic parent status and sex of proband were considered, certain interactions between 5HTTLPR and other genetic risk factors were evident. One type of interaction with the LL variant of 5HTTLPR increased externalizing behavior in individuals with antisocial biologic parentage; a second interaction with one or more 5HTTLPR short variants (SS or SL) appeared to increase externalizing behaviors in conjunction with a genetic diathesis for alcoholism. Gender of adoptee also appeared to interact with 5HTTLPR. Male individuals with the short variant were more likely to have higher symptom counts for conduct disorder, aggressivity, and ADHD. In contrast, among females, the short variant (SS, SL) was associated with lower levels of such behavior. The results support the hypothesis that gene-biological family history interactions are involved in the externalizing behaviors studied and constitute interesting findings for future replication.     

Meta-analysis of association between PITX3 gene polymorphism and Parkinson's disease

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Several studies had researched the association between the PITX3 gene polymorphism and Parkinson's disease. However, the results were inconsistent. To evaluate whether PITX3 gene polymorphism is involved in the risk of PD we conducted this meta-analysis. All the eligible studies were searched from the databases of Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index EXPANDED in any languages up to May 2011. Finally ten studies about PITX3 gene including 5172 patients and 7290 controls were identified for meta-analysis. Meta-analysis was carried out to evaluate whether PITX3 gene polymorphism was associated with PD, and subgroup analysis was also performed when necessary. This meta-analysis finds that rs4919621 allele A was significantly associated with PD in the Caucasian population (P=0.04,). Subgroup analysis of early onset PD (EOPD) and late onset PD (LOPD) revealed that the rs2281983 allele C and rs4919621 allele A were significantly associated with the risk of PD (all of the P values were ≤ 0.0001) in EOPD population. This research indicated that the presence of the rs4919621 allele A significantly increased the risk of PD patients in Caucasian population while rs2281983 allele C and rs4919621 allele A were both risk factors in EOPD.     

Poly (ADP-ribose) polymerase-1 (PARP-1) genetic variants are protective against Parkinson's disease

Poly (ADP-ribose) polymerase-1 (PARP-1) is involved in crucial pathogenic events in Parkinson's disease (PD). We studied the effect of promoter variations of PARP-1 gene on the risk for PD in a case-control association study comprising 146 PD patients and 161 controls from Northern Spain. Three polymorphisms from the promoter region of PARP-1 gene were analyzed: -410C/T, -1672G/A, and a (CA)n microsatellite. A protective effect against PD was found for heterozygosity at (-410) (OR 0.44) and (CA)n microsatellite (OR 0.53) polymorphisms, and heterozygosity at (-1672) polymorphism delayed by 4 years on the onset age of PD. Variations in the regulatory region of PARP-1 gene might modify the risk for PD.