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体易患精神病理学和酗酒中的作用。我们强调的是功能等位基因在行为中的作用。两个5-HT 1A变体是罕见的氨基酸取代（Gly 22 Ser和Val 28 Ile），一个保守，一个非保守。5-HT 2C变异是一种常见的（等位基因频率=0.18）非保守性取代（Cys 23 Ser）。两个5 HT 2A氨基酸取代（Ala 477 Val和His 452 Tyr）具有0.01和0.09的等位基因频率。还发现了罕见的5-羟色胺转运体和5-HT 7氨基酸取代。当在CHO-K1细胞中表达时，5 HT 1A Gly 22 Ser显著改变了这些受体的脱敏和下调。5 HT 2C Cys 23 Ser在卵母细胞和COS-7细胞中降低配体结合。5 HT 2A His 452 Tyr损害来自具有452 Tyr等位基因的受试者的血小板中的信号转导。最近发现了一个新的TPH基因TPH 2，该基因编码脑特异性TPH。通过重测序，我们确定了TPH 2中一个不常见的氨基酸取代。多位点TPH 2单倍型与多个人群中的自杀倾向相关，并与CSF 5 HIAA（脑5-羟色胺周转指数）水平低相关。一个新的TPH 2错义等位基因报告，并与抑郁症的卡隆组无法检测到。在芬兰人中发现了5 HT 1B（5-羟色胺神经元的终末自身受体）与反社会酒精中毒的同胞配对联系，并在美国西南部印第安人中复制[Lappalainen et al]。在一系列出版物中，我们表明5 HT 2A-1438 G>A启动子变体与焦虑相关病症相关。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的焦虑相关量表。检测到5 HT 5氨基酸取代，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）通过突触前神经元对5-羟色胺的Na依赖性摄取在突触能神经传递的终止中起关键作用，并且5-HTT启动子（HTTLPR）的功能显著多态性是精神病遗传学中研究最多的位点。多态性影响体外5-HTT转录，并最终影响5-HTT功能。我们在同胞对分析中将HTTLPR与TPQ的两个焦虑相关分量表联系起来（C。Mazzanti），复制了Lesch及其同事的早期发现。该变异体还与SAD [以诺等人]、酒精反应[Schuckit等人]和精神分裂症的BPRS精神病性评级[Malhotra等人]相关。5-羟色胺转运蛋白多态性与连接功能基因变异与行为的因果链中的两个中间表型有关。这些是通过B-CIT SPECT测定的中脑5-羟色胺转运蛋白密度[海因茨等人]和认知恐惧挑战后的杏仁核代谢活性[Hariri等人]。我们在一个大型NIMH病例/对照数据集中发现了HTTLPR中的一个新的功能等位基因，并将功能基因型的获得与强迫症联系起来（D。Murphy）和来自多伦多大学的由父母-子女三人组组成的传播不平衡数据集（J. Kennedy）。这个新的等位基因，L等位基因中的A>G SNP，产生了改变转录的功能性AP 2位点。在LNG中也发现了一种罕见的5-羟色胺转运蛋白错义变体，NIMH的同事证明了它的功能，NIMH和西方精神病研究所的合作者在两个家庭中进行了研究。在这些家族中，HTT变异预示着更严重的行为综合征，可能包括强迫症、焦虑和显性遗传综合征。

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.