5-羟色胺转运体启动子区基因多态性与强迫症的关联分析

目的:探索汉族人群中的5-羟色胺转运体启动子区(5-HTTLPR)基因多态性与强迫症的发病关系.方法:对强迫症患者(强迫症组)和正常对照者(对照组)分别采用聚合酶链反应扩增片断长度多态技术测定基因型.结果:强迫症组与对照组5-HTTLPR的基因型频率无显著性差异;两组的等位基因频率有显著性差异.L等位基因与强迫症呈正关联(OR=1.929,P＜0.05).结论:5-HTTLPR基因多态性的L等位基因与强迫症相关联,是强迫症的危险因子.     

Significance of serotonin transporter gene 5-HTTLPR and variable number of tandem repeat polymorphism in attention deficit hyperactivity disorder

The purpose of this study was to evaluate the relationship between attention deficit hyperactivity disorder (ADHD) and polymorphism of the two regions of the 5-HTT gene [variable number of tandem repeats (VNTR) and 5-HTTLRR] in a sample of Turkish children. Using the PCR technique, these polymorphisms were assessed in 71 patients with ADHD and 128 healthy controls. The 5-HTTLPR S/S genotype was significantly lower in the patients than in the controls (p = 0.018). Homozygous and heterozygous L variant predominated in the ADHD group. But the VNTR STin2.12/12 genotype was significantly less found in the patients than in the controls (p = 0.001). There was no significant difference between the frequency of the short (S), long, 10, and 12 alleles of both groups. The lack of an S/S variant of 5-HTTLPR polymorphism of the STin2.12/12 variant of VNTR polymorphism appears to be associated with an increased risk of ADHD.     

5-羟色胺转运体基因多态与共患学习困难的儿童注意缺陷多动障碍的相关性

目的探讨共患学习困难(LD)的注意缺陷多动障碍(ADHD)患儿与5-羟色胺转运体(5-HTT)基因连锁多态区(5-HTTLPR)和第2内含子17 bp数目可变的顺向重复(stin2.VNTR)的关联关系。方法对126例共患LD的ADHD患儿和198例不共患LD的ADHD患儿的5-HTTLPR和stin2.VNTR两种多态进行检测,并采用传递不平衡检测(TDT)和单体型分析方法进行关联分析。结果(1)TDT检测:5-HTTLPR多态的S等位基因在共患LD的ADHD和ADHD混合型(ADHD-C)核心家系中优先传递(X2=5.831和5.281,P=0.015和0.020);所有家系均未观察到stin2.VNTR多态中的任何等位基因有传递不平衡现象(均P>0.05);(2)单体型分析:5-HTT基因与共患LD的ADHD和ADHD-C相关联(X2=11.391和13.343,v=3,P=0.010和P=0.004);单体型L／12在共患LD的ADHD和ADHD-C核心家系中传递较少(X2=10.317和8.948,v=1,P=0.001和0.003),而单体型L／10在共患LD的ADHD核心家系中传递较多(X2=4.065,v=1,P=0.044)。结论5-HTT基因可能与共患LD的ADHD相关联,其中主要为共患LD的ADHD-C亚型。     

Familial links between attention deficit hyperactivity disorder, conduct disorder, and bipolar disorder

Although family, twin, and adoption studies indicate that attention deficit hyperactivity disorder (ADHD) is a familial condition with a robust genetic component, molecular genetic studies of candidate genes have produced inconsistent findings. One of the challenges to elucidating the genetic architecture of ADHD is its potential genetic heterogeneity. Therefore, efforts are needed to identify etiologically homogenous subgroups of subjects with ADHD for use in genetic studies. The current article reviews evidence suggesting that parsing ADHD subjects based on comorbidity with conduct and bipolar disorders may yield familial subtypes that are suitable for genetic analyses.     

Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder.

Although modulation of symptoms of obsessive-compulsive disorder (OCD) by serotonergic agents is well established, it is unclear whether an abnormality in the central serotonergic system is involved in its etiology. The serotonin (5-HT) transporter (5-HTT), which is the key modulator of serotonergic neurotransmission, is the target for serotonin reuptake inhibiting drugs (SRIs) that are uniquely effective in the treatment of OCD. In this preliminary study we report an association of a functional polymorphism in the 5-HTT 5' regulatory-region and OCD. Seventy-five OCD Caucasian patients and 397 ethnically-matched individuals from a non-patient control group were genotyped for the 5-HTTLPR. Population-based association analysis revealed that patients with OCD were more likely to carry two copies of the long allele (l) as compared to controls (46.7% vs 32.3%: chi2 = 5.19, P = 0.023). This finding replicates a recent family-based study of this polymorphism in OCD, and thus indicates that the 5-HTTLPR may be associated with susceptibility to OCD.     

Association of the serotonin transporter promoter region polymorphism with biased attention for negative word stimuli

Background: Biased attention for emotional stimuli reflects vulnerability or resilience to emotional disorders. The current study examines whether the 5‐HTTLPR polymorphism is associated with attentional biases for negative word stimuli. Methods: Unmedicated, young adults with low current depression and anxiety symptoms (N=106) were genotyped for the 5‐HTTLPR, including the single nucleotide polymorphism (SNP) rs25531 in the long allele of the 5‐HTTLPR. Participants then completed a standard dot‐probe task that measured attentional bias toward anxiety, dysphoric, and self‐esteem words. Results: The L_AL_A allele group demonstrated an attentional bias away from negative word stimuli. This attentional bias was absent among the S/L_G carriers. Conclusions: These findings replicate previous work and suggest that 5‐HTTLPR L_A homozygotes possess a protective attentional bias that may decrease susceptibility to depression and anxiety. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

多巴胺D4受体基因和5-羟色胺转运体基因与注意缺陷多动障碍及其相关症状的关联分析

目的 探讨多巴胺D4受体(DRD4)基因和5-羟色胺转运体(5-HTT)基因与注意缺陷多动障碍(ADHD)及其相关症状的关系.方法利用Achenbach父母用儿童行为调查表评定139例ADHD患儿(患者组)的临床症状;采用聚合酶链反应、聚丙烯酰胺凝胶电泳结合银染技术,检测患者组和115名正常儿童(对照组)的基因型和等位基因频率.结果 (1)患者组与对照组间DRD4和5-HTT基因的基因型及等位基因频率分布的差异无统计学意义(P>0.05).(2)5-HTT基因的S/S基因型个体的社会退缩[(4.4±3.0)分]、躯体主诉[(3.6±2.7)分]得分高于S/L+L/L基因型个体[(3.3±2.6)分和(2.6±2.6)分],差异有统计学意义(P<0.05).(3)在非携带DRD4基因3等位基因个体中,S/L+L/L基因型的注意问题[(10.4±3.1)分]和社交问题[(7.2±3.7)分]得分高于S/S基因型个体[分别为(8.7±3.1)分和(5.3±2.3)分],差异有统计学意义(P<0.05).结论 DRD4基因和5-HTT基因与ADHD可能无关联;但5-HTT基因与ADHD的某些内化性症状可能存在关联;对ADHD的某些症状(注意问题和社交问题),DRD4基因与5-HTT可能存在相互协同作用.     

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP_ND) in patients with ADHD and to assess associations of SERT BP_ND between the brain regions. 25 medication‐free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [¹¹C]DASB. SERT BP_ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP_ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP_ND and age in the ADHD and the healthy control group, we confirmed an age‐related decline in brain SERT binding in the thalamus and insula (R² = 0.284, R² = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792–802, 2017. © 2016 Wiley Periodicals, Inc.     

Associations of serotonin transporter gene promoter polymorphisms and monoamine oxidase A gene polymorphisms with oppositional defiant disorder in a Chinese Han population

Background

Oppositional defiant disorder (ODD) is a behavioral disorder that mainly refers to a recurrent pattern of disobedient, defiant, negativistic and hostile behaviors toward authority figures. Previous studies have showed associations of serotonin transporter (5-HTT) and monoamine oxidase A (MAOA) with behavioral and psychiatric disorders. The purposes of this study were to investigate the potential association of 5-HTT gene promoter polymorphism (5-HTTLPR) and MAOA gene polymorphism with susceptibility to ODD in a Han Chinese school population.

Methods

The 5-HTTLPR gene polymorphism and the MAOA gene polymorphism were genotyped in a case–control study of 257 Han Chinese children (123 ODD and 134 healthy controls).

Results

There was significant difference in the allele distribution of 5-HTTLPR (χ²?=?7.849, P?=?0.005) between the ODD and control groups. Further, there were significant differences in genotype (χ²?=?5.168, P?=?0.023) and allele distributions (χ²?=?10.336, P?=?0.001) of the MAOA gene polymorphism that is variable-number tandem repeat (MAOA-uVNTR) between two groups. Moreover, there were significant differences in genotype (χ²?=?4.624, P?=?0.032) and allele distributions (χ²?=?9.248, P?=?0.002) of MAOA-uVNTR only in the male ODD and healthy groups.

Conclusions

Our results suggest that 5-HTTLPR and MAOA-uVNTR gene variants may contribute to susceptibility to ODD. Further, MAOA-uVNTR gene polymorphism may play a role in susceptibility to ODD only in male children.

     

Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. Serotonergic dysfunction has been implicated in PTSD. The present study examined the possible association between the serotonin-transporter-linked polymorphic region (SERTPR) and PTSD. The genotype and allele frequencies of the SERTPR were analyzed in 100 PTSD patients and 197 unrelated healthy controls using a case-control design. The frequency of the s/s genotype was significantly higher in PTSD patients than in normal controls. These findings suggest that the SERTPR s/s genotype is one of the genetic factors for the susceptibility to PTSD. Further investigations are required into the influence of gene polymorphisms on the biological mechanisms of PTSD, its clinical expression, and its response to treatment.     

Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder

Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly better for the s/s genotype of the 5-HTTLPR polymorphism than for l-allele carriers. These results support our hypothesis that the response to noradrenergic and specific serotonergic antidepressants is significantly associated with the 5-HTTLPR polymorphism.     

Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders

OBJECTIVE: Attention deficit hyperactivity disorder is a heterogeneous disorder of unknown etiology. Little is known about the comorbidity of this disorder with disorders other than conduct. Therefore, the authors made a systematic search of the psychiatric and psychological literature for empirical studies dealing with the comorbidity of attention deficit hyperactivity disorder with other disorders. DATA COLLECTION: The search terms included hyperactivity, hyperkinesis, attention deficit disorder, and attention deficit hyperactivity disorder, cross-referenced with antisocial disorder (aggression, conduct disorder, antisocial disorder), depression (depression, mania, depressive disorder, bipolar), anxiety (anxiety disorder, anxiety), learning problems (learning, learning disability, academic achievement), substance abuse (alcoholism, drug abuse), mental retardation, and Tourette's disorder. FINDINGS: The literature supports considerable comorbidity of attention deficit hyperactivity disorder with conduct disorder, oppositional defiant disorder, mood disorders, anxiety disorders, learning disabilities, and other disorders, such as mental retardation, Tourette's syndrome, and borderline personality disorder. CONCLUSIONS: Subgroups of children with attention deficit hyperactivity disorder might be delineated on the basis of the disorder's comorbidity with other disorders. These subgroups may have differing risk factors, clinical courses, and pharmacological responses. Thus, their proper identification may lead to refinements in preventive and treatment strategies. Investigation of these issues should help to clarify the etiology, course, and outcome of attention deficit hyperactivity disorder.     

Obsessive-compulsive disorder, factor-analyzed symptom dimensions and serotonin transporter polymorphism

Recently, on the basis of the effects of serotonin (5-HT) reuptake inhibitors in obsessive-compulsive disorder (OCD) treatment, several candidate genes related to 5-HT regulation have been hypothesized to play an important role in the development of OCD. One of them is 5-HT transporter gene. Therefore, the aims of this study were to investigate the associations between 5-HT transporter polymorphism and OCD. One hundred and twenty-four OCD patients and 171 normal controls participated in this study. Genomic DNA was extracted from their blood. Comparison of the genotypes and allele frequencies of the SERTPR polymorphism between the OCD group and the control group was made. Using principal component analysis, we derived four factors from thirteen main contents of the Y-BOCS checklist and investigated the association between these four factors and the SERTPR polymorphism. In this case-control study, we could not find any associations between the SERTPR polymorphism and the development of OCD. In the OCD group, patients with the L genotype had higher scores for the religious/somatic factor than with the S genotype. In conclusion, the SERTPR polymorphism does not affect the development of OCD. But SERTPR polymorphisms affect certain factors of OC symptoms. Moreover, the factor analytic approach used in the present study has identified meaningful symptom dimensions to help guide future research.     

The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder

There is evidence that abnormalities within the dopamine system in the brain play a major role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). For instance, dopaminergic psychostimulants, the drugs of first choice in ADHD, interact directly with the dopamine transporter (DAT). Molecular genetic studies suggest involvement of a polymorphism of the DAT gene in ADHD. More recent imaging studies show abnormalities in various brain structures, but particularly in striatal regions. In the current paper we review recent studies in this area. First in vivo measurements of DAT with single photon emission computed tomography (SPECT) in ADHD patients revealed an elevation of striatal DAT density. No differences in DAT density between the left and right side and between putamen and caudate nucleus have been found in [99mTc]TRODAT-1 SPECT of ADHD patients. Patients with ADHD and with a history of nicotine abuse both displayed lower values of DAT density in [99mTc]TRODAT-1 SPECT than non-smokers with ADHD. DAT seem to be elevated in non-smoking ADHD patients suffering from the purely inattentive subtype of ADHD as well as in those with the combined or purely hyperactive/impulsive subtype.     

Circulatory levels of catecholamines, serotonin and lipids in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) may be associated with a dysregulation of the catecholaminergic and serotonergic systems. Furthermore, ADHD is frequently complicated by aggressive impulsive behaviour, which is suggested to be related to low serum cholesterol levels. We examined the relationship between blood serotonin, norepinephrine, dopa and lipid levels and the degree of hyperactivity, impulsiveness, lack of concentration, and aggressiveness in boys with ADHD of low and high severity as determined by a specially designed formulated scale based on the DSM-IV criteria for ADHD. No differences were noted between the groups in any of the peripheral biological parameters except blood serotonin, for which a tendency (P=0.08) towards lower levels was observed in the children with more severe disorder. We conclude that children with severe ADHD may have a different serotonin turnover compared to children with mild ADHD. These results may have implications for our understanding of the pathogenesis of ADHD, at least the more severe type.     

Relation of attention deficit and conduct disorder to vigilance and reading lag

The relationship between DSM-III Axis I diagnoses 'attention deficit disorder with hyperactivity' (ADDH), 'conduct disorder' (CD) and 'anxiety disorder' (AD) and measures of attention and reading were studied in 158 children. Children diagnosed as having severe or moderate ADDH were found to be younger at referral and to have a lower IQ than were children with CD and AD. When age, IQ, social class and sex were controlled, children with severe ADDH were found to perform significantly worse than other diagnostic groups on some tests of vigilance and reading age. The data suggest that children with severe ADDH form a distinct group, and those with mild ADDH overlap symptomatically and on tests of vigilance with children with CD.     

Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder

OBJECTIVE: The authors examined whether patients with attention deficit hyperactivity disorder (ADHD) have altered striatal dopamine transporter levels, which may explain psychostimulant effects in this disorder. METHOD: Single photon emission computed tomography and [(123)I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([(123)I]beta-CIT) were used to assess dopamine transporter availability in nine adult patients with ADHD (eight of whom were stimulant naive) and nine age- and gender-matched healthy comparison subjects. RESULTS: Striatal [(123)I]beta-CIT binding did not differ significantly between the ADHD and comparison subjects. CONCLUSIONS: The findings suggest that a hypothesized dysregulation of dopamine function in ADHD does not entail altered dopamine transporter levels.