Molecular Genetic Studies Of Serotonin Function

对具有5-羟色胺功能遗传变异的个体和动物的研究揭示了这种神经递质在行为中的作用，包括5-羟色胺基因的功能变异在使个人易患精神疾病和酗酒方面的作用。我们强调功能性[候选]等位基因在行为中的作用。两个5-HT1a变异体是罕见的氨基酸替换(Gly22Ser和Val28Ile)，一个保守，一个非保守。5-HT2C变异是一种常见的(等位基因频率=0.18)非保守替换(Cys23Ser)。两个5HT2A氨基酸替换(Ala477Val和His452Tyr)的等位基因频率分别为0.01和0.09。还发现了罕见的5-羟色胺转运体和5-HT7氨基酸替换。当5HT1AGly22Ser在CHO-K1细胞中表达时，显著改变了这些受体的脱敏和下调。5HT2C Cys23Ser在卵母细胞和COS-7细胞中的配体结合减少。5HT2AHis452Tyr损伤了携带452Tyr等位基因的受试者的血小板信号转导。最近发现了一种新的TPH基因TPH2，该基因编码一种脑特异性TPH。通过重新测序，我们发现了TPH2中一个不常见的氨基酸替换。多位点TPH2单倍型与多个人群的自杀倾向以及脑脊液5HIAA的低水平有关，5HIAA是脑5-羟色胺代谢的指标。Caron小组报告的与抑郁症相关的一种新的TPH2错义等位基因未被检测到。5-HT1b(5-羟色胺神经元的末端自身受体)与反社会酒精中毒的SIB对链接在芬兰人中被发现，并在美国西南部印第安人中复制[Lappalainen等人]。在一系列文献中，我们发现5HT2A-1438G&gt；A启动子变异体与焦虑相关疾病有关。这些包括强迫症、季节性情感障碍、神经性厌食症和三维人格问卷中与焦虑相关的量表。检测到5HT5氨基酸替换，并揭示了与精神分裂症的初步连锁信号[岩田等人]。5-羟色胺转运体(5-HTT)在5-羟色胺能神经递质的终止过程中起着重要作用，5-HTT启动子的功能显著多态(HTTLPR)是精神病学遗传学中研究最多的基因。这种多态在体外会影响5-HTT的转录，最终影响5-HTT的功能。我们在同胞配对分析(C.Mazzanti)中将HTTLPR与TPQ中与焦虑相关的两个子量表联系起来，复制了Lesch和他的同事早期的发现。该变异还与SAD[Enoch等人]、酒精反应[Schuckit等人]和精神分裂症的BPRS精神病评分[Malhotra等人]有关。5-羟色胺转运体的多态接下来与连接功能基因变异和行为的因果链条中的两个中间表型联系在一起。这些是由B-CIT SPECT确定的中脑5-羟色胺转运体密度[Heinz等人]和认知恐惧挑战后杏仁核的代谢活动[Hariri等人]。我们在HTTLPR中发现了一个新的功能等位基因，并在一个大的NIMH病例/对照数据集(D.Murphy)和来自大学的传播不平衡数据集中将功能基因型的获得与强迫症联系起来。多伦多的由亲子三人组组成的(J.肯尼迪)这个新的等位基因是L等位基因中的一个A&GT；G SNP，它创建了一个改变转录的功能性AP2位点。NIMH的同事们也在LNG中发现了一种罕见的5-羟色胺转运体错义变体，并由NIMH和西方精神病学研究所的合作者在两个家庭中进行了研究。在这些家庭中，HTT变异预示着更严重的行为综合征，可能包括强迫症、焦虑症和明显的阿斯伯格综合症。

Studies on individuals and animals with genetic variants in serotonin function shed light on the role of this neurotransmitter in behavior including the role of functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are emphasizing the role of functional [candidate] alleles in behavior. Two 5-HT1A variants are rare amino acid substitutions (Gly22Ser and Val28Ile), one conservative and one nonconservative. The 5-HT2C variant is a common (allele frequency=0.18) nonconservative substitution (Cys23Ser). Two 5HT2A amino acid substitutions (Ala477Val and His452Tyr) have allele frequencies of 0.01 and 0.09. Rare serotonin transporter and 5-HT7 amino acid substitutions were also discovered. 5HT1A Gly22Ser when expressed in CHO-K1 cells dramatically altered desensitization and down regulation of these receptors. 5HT2C Cys23Ser in oocytes and COS-7 cells decreased ligand binding. 5HT2A His452Tyr impaired signal transduction in platelets from subjects with the 452Tyr allele. Recently a new TPH gene, TPH2, was detected and this gene encodes a brain-specific TPH. By resequencing, we identified an uncommon amino acid substitution in TPH2. A multilocus TPH2 haplotype was linked to suicidality in multiple populations, and to low levels of CSF 5HIAA, an index of brain serotonin turnover. A novel TPH2 missense allele reported and linked to depression by the Caron group could not be detected. Sib-pair linkage of 5HT1B, the terminal autoreceptor for serotonin neurons] to antisocial alcoholism was found in Finns and replicated in Southwestern American Indians [Lappalainen et al]. In a series of publications, we showed that the 5HT2A-1438 G>A promoter variant is linked to anxiety related conditions. These include OCD, seasonal affective disorder, anorexia nervosa and anxiety-related scales from the Tridimensional Personality Questionnaire. A 5HT5 amino acid substitution was detected and reveals a preliminary linkage signal to schizophrenia [Iwata et al]. The serotonin transporter (5-HTT) plays a critical role in the termination of serotonergic neurotransmission by Na-dependent uptake of serotonin by the presynaptic neuron and a functionally significant polymorphism in the 5-HTT promoter (HTTLPR) is the most studied locus in psychiatric genetics. The polymorphism affects in vitro 5-HTT transcription and, ultimately, 5-HTT function. We linked HTTLPR to the two anxiety related subscales of the TPQ in a sib pair analysis (C. Mazzanti), replicating the earlier finding by Lesch and colleagues. The variant was also linked to SAD [Enoch et al], alcohol response [Schuckit et al], and BPRS psychoticsm rating in schizophrenia [Malhotra et al]. The serotonin transporter polymorphism was next linked to two intermediate phenotypes in the causal chain connecting functional gene variant to behavior. These were midbrain serotonin transporter density determined by B-CIT SPECT [Heinz et al] and amygdala metabolic activity following a cognitive fear challenge [Hariri et al]. We discovered a new functional allele in HTTLPR and linked gain of function genotypes to OCD, in a large NIMH case/control dataset (D. Murphy) and a transmission disequilibrium dataset from the Univ. of Toronto consisting of parent-child trios (J. Kennedy). This new allele, an A>G SNP in the L allele, creates a functional AP2 site altering transcription. A rare serotonin transporter missense variant was also discovered in LNG, shown to be functional by NIMH colleagues, and studied in two families by collaborators in NIMH and at Western Psychiatric Institute. In these families, the HTT variant predicts a more severe behavioral syndrome which may include obsessionality, anxiety, and overt Asperger's syndrome.