The HOPA Gene Dodecamer Duplication Is Not a Significant Etiological Factor in Autism

A recent study has suggested that a dodecamer duplication in the HOPA gene in Xq13 may occur in a significant portion of male patients with autism. We have determined the incidence of this duplication in 202 patients from the South Carolina Autism Study. The incidence of the duplication was not significantly different between patients and controls. Three of the female patients inherited the duplication from nonautistic fathers. In addition, there was no systematic skewing of X inactivation in the female patients with the duplication, or in nonautistic mothers and sisters with the duplication. These findings suggest that the dodecamer duplication in the HOPA gene does not play a significant role in the etiology of autism.     

Turner syndrome and schizophrenia: A further hint for the role of the X-chromosome in the pathogenesis of schizophrenic disorders

Abnormalities of sex chromosomes are associated with various forms of neuropsychiatric disorders, such as schizophrenia. Turner syndrome occurs approximately threefold more frequently in female schizophrenics compared to the general female population. A single case is reported. We report on a case of a 41-year-old woman with Turner syndrome, schizophrenia, mental retardation, and hypothyroidism. A polymorphism of the HOPA gene within Xq13 termed HOPA^12bp is associated with schizophrenia, mental retardation, and hypothyroidism. Interestingly, Xq13 is the X-chromosome region that contains the X-inactivation center and a gene escaping X-inactivation whose gene product may be involved in the X-inactivation process as well as in the pathogenesis of sex chromosome anomalies such as Turner syndrome. These genes that escape X-inactivation may produce their gene products in excess, influencing normal brain growth and differentiation. Our case gives a further hint for an involvement of the X-chromosome in the pathogenesis of schizophrenia.     

The association of a HOPA polymorphism with major depression and phobia

Thyroid hormone has a prominent role in the development and homeostasis of the central nervous system (CNS). Consequently, genes participating in thyroid hormone receptor (THR)-mediated signal transduction are prime candidates for neuropsychiatric illness susceptibility factors. Previously, we have associated exonic polymorphisms in a Xq13 thyroid receptor coactivator named HOPA with a modest increase in vulnerability to a broad spectrum of neuropsychiatric illness, including depression, psychosis, and hypothyroidism. In order to test and extend these findings, we have now examined the relationship between HOPA polymorphisms and neuropsychiatric illness in a cohort of Iowa adoptees. Consistent with our prior findings, HOPA polymorphisms were associated with an increased risk for major depression. There was suggestive evidence that the increased psychiatric morbidity in these subjects could represent epistasis, e.g., an interaction between the HOPA variant and a genetic diathesis for another psychiatric condition such as biologic parent antisocial behavior. Information about biologic parent behavior and the adoptive home environment was used to determine depressive symptoms attributable to gene-environment interaction. HOPA variant subjects continued to show significant differences in depressive symptoms when controlling for gene-environment interaction. Finally, because obesity is associated with hypothyroidism and HOPA polymorphisms are associated with hypothyroidism, we analyzed weight with respect to HOPA allele status. We found that that HOPA polymorphisms were associated with increased risk for obesity (P <.001). In summary, we conclude that HOPA polymorphisms may be a moderate risk factor for increased susceptibility to a broad spectrum of neuropsychiatric illness and hypothesize that the type of illness manifested might be related to a separate genetic diathesis.     

Copy number variation and schizophrenia

Over the last 12 months, a series of major articles have reported associations with schizophrenia of copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 22q12, and Neurexin 1 loci. These are rare high-penetrant mutations that increase risk not only of schizophrenia but also of a range of other psychiatric disorders including autism and mental retardation. In some cases, the same phenotype can occur irrespective of whether the copy number variant causes a deletion or duplication. Some of these mutations occur at very high rates in human populations, but because of reduced fecundity associated with major psychiatric disorders the overall frequency in the population remains low. These new findings raise fundamental clinical and scientific questions concerning classification of major neuropsychiatric disorders, modes of inheritance, diagnostics, and genetic counseling. Although the loci identified so far account for only a small proportion of cases, many more are likely to be discovered over the next few years. A major focus of research will be to identify the key, the genetic and environmental determinants of schizophrenia risk in carriers of these copy number variants, and to discover whether their rates of mutation are unstable or fixed.     

Serotonin transporter polymorphisms: no association with response to antipsychotic treatment, but associations with the schizoparanoid and residual subtypes of schizophrenia

The human serotonin transporter gene (5-HTT) demonstrates two polymorphisms with possible functional impact: a 44-bp insertion/deletion polymorphism of the promoter region and a 17-bp variable number of tandem repeat polymorphism (VNTR) in intron 2 (STin2). Such genetic polymorphisms in the serotoninergic system may increase the susceptibility to schizophrenia or may serve as predictors of therapeutic response. We therefore analyzed these polymorphisms as susceptibility factors for schizophrenia by comparison of 684 schizophrenic inpatients with 587 healthy controls. We furthermore compared the therapeutic outcome of schizophrenic patients differentiated by the 5-HTT genotypes. Schizo-affective patients were more frequently homozygous for the 44-bp insertion allele (Odds ratio, OR: 1.6, 95% confidence interval, CI: 1.1--2.3, P < 0.03) than were all other schizophrenic patients and controls. The 17-bp VNTR alleles found were: STin2.7, 9, 10, and 12. Sequence analysis revealed seven different sequence motifs with an invariable arrangement. Patients with schizo-paranoid schizophrenia were more frequently homozygous for the STin2.12 allele than were controls (OR: 1.4, CI: 1.1--1.8, P < 0.007) and all other schizophrenic patients (OR: 1.6, CI: 1.2--2.3). The STin2.9 allele represented a risk factor for the residual subtype of schizophrenia (OR: 6.4, CI: 2.5--16.2, P < 0.001). On the basis of global clinical impressions, as well as measurements with the positive and negative syndrome scale we found no association of the polymorphisms with therapeutic response. In conclusion, the 44-bp polymorphism may be associated with the schizo-affective and the 17-bp VNTR with the residual and schizo-paranoid subtype of schizophrenia, findings which require further biochemical and epidemiological confirmation.     

Association study of a nicotinic receptor variant with schizophrenic disorders

Nicotine acetylcholine receptors (nAChRs) are implicated in the pathogenesis of schizophrenia because the prevalence of smoking among schizophrenic patients is extraordinarily high, and nicotine has been demonstrated to improve some psychophysiological dysfunction in schizophrenics. In addition, recent studies have suggested linkage of the alpha(7) nAChR gene region in families of schizophrenics. In a population-based association study, we tested the hypothesis that the allelic variant, with a 2-bp deletion, of the human alpha(7) nAChR gene confers susceptibility to schizophrenic disorders. We genotyped alpha(7) nAChR in 146 patients with schizophrenic disorders and 151 controls. The results showed no significant difference in genotype or allele frequencies between schizophrenic patients and control subjects. This suggests that alpha(7) nAChR 2-bp deletion plays no major role in the pathogenesis of schizophrenic disorders. Other nAChR variants in schizophrenic disorders may need further investigation.     

Association for serotonin transporter gene variable number tandem repeat polymorphism and schizophrenic disorders

In contrast with two previous western reports, a recent study on a Chinese population found an association for allele 12 of the variable number tandem repeat (VNTR) in the second intron of the serotonin transporter (5-HTT) gene and schizophrenic disorders. We have replicated this finding for a Chinese population in Taiwan (114 schizophrenic patients and 127 controls), demonstrating a modest but significant statistical association for the 5-HTT-VNTR allele 12 and schizophrenic patients (one-sided p = 0.043). This positive finding further supports the proposition that the 5-HTT-VNTR allele 12 is a risk factor for schizophrenic disorders in Chinese populations, although the effect is weak.     

A novel mutation of the ARX gene in a male with nonsyndromic mental retardation

ARX (Aristaless-related homeobox gene) is located at Xp22. It contains 5 exons and encodes a 562-amino acid protein. The protein contains 4 polyalanine tracts, 3 of which are encoded in exon 2 and 1 in exon 4. Mutations in the ARX gene have been found in X-linked infantile spasms syndrome, Partington syndrome (mental retardation with dystonic movements of the hands), X-linked lissencephaly with abnormal genitalia, X-linked myoclonus epilepsy with spasticity and intellectual disability, and in nonsyndromic X-linked mental retardation. The most common mutation in ARX (seen in X-linked infantile spasms syndrome, Partington syndrome, and X-linked mental retardation) is a 24-bp duplication in exon 2 resulting in expansion of a polyalanine tract. Truncating mutations (deletions, frameshift, non-sense) have been found in X-linked lissencephaly with abnormal genitalia, as well as homeodomain missense mutations in X-linked myoclonus epilepsy with spasticity and intellectual disability. The authors report a novel 24-bp in-frame deletion within exon 2 of the ARX gene in a male child with X-linked mental retardation and review the spectrum of ARX mutations. This mutation results in a contraction of the second polyalanine repeat.     

IL18R1基因多态性与中国汉族精神分裂症的关联性分析

目的:探讨IL18受体IL18R1基因多态性与中国汉族精神分裂症的关系。方法:采用病例对照研究方法,选取1 174例精神分裂症患者(病例组)与1 120名正常健康对照者(对照组),利用连接酶检测-聚合酶链反应(LDR-PCR)方法对IL18R1基因多态位点rs1035130进行基因分型,观察其等位基因及基因型与精神分裂症发病风险的关系。结果:rs1035130的基因型与等位基因频率在病例组与正常对照组中的分布差异无统计学意义(P0.05)。结论:IL18R1基因rs1035130多态性可能与中国汉族精神分裂症无关。     

Association Between a Casein Kinase 1 Epsilon Gene Polymorphism and Schizophrenia in a Chinese Han Population

The casein kinase 1 (Csnk1) family of serine/threonine kinases regulates dopamine receptor (DR) signaling by phosphorylating the 32-kDa dopamine- and cAMP-regulated phosphoprotein DARPP-32, leading to inhibition of protein phosphatase 1 and a shift in the phosphorylation state of many downstream proteins. By modulating DR-activated phosphorylation cascades, Csnk1 plays a central role in neuropsychiatric disorders and modulates the stimulant response to amphetamine. No published study, however, has established a correlation between Csnk1 gene polymorphisms and schizophrenia. We genotyped the rs135745C/G polymorphism of the Csnk1ε gene in 384 schizophrenic patients and 502 healthy controls drawn from the Chinese Han population. There were significantly higher CG and CC genotype frequencies in schizophrenic patients compared to control subjects (CG, p?=?0.0086, odds ratio (OR)?=?1.477, 95% confidence interval (CI), 1.103-1.978; CC, p?=?0.0431, OR?=?2.571; 95% CI, 0.998-6.624). The C allele frequency was also higher in the schizophrenics (p?=?0.0022; OR?=?1.474; 95% CI, 1.149-1.891). In the dominant model, subjects with genotypes CC or CG were at greater risk for schizophrenia (p?=?0.0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1ε gene significantly enhances the probability of schizophrenia in the Chinese Han population.     

Distribution of androgen receptor CAG repeat polymorphism in Chinese schizophrenia and its correlation with age at onset

The action of androgens is mediated by the androgen receptors (ARs), which are located throughout the brain. The AR gene is implicated in the pathogenesis of schizophrenia because male siblings with schizophrenia share alleles at this gene at a rate higher than chance predicts, and differences in sex hormone function may explain the gender difference in schizophrenic manifestations. Since the shorter alleles of the AR CAG repeat polymorphism are associated with increased gene expression, we tested the hypothesis that the AR CAG repeat variant confers susceptibility to schizophrenia using a sample of 225 people with schizophrenia and 247 normal controls. Using the median AR repeat length in the normal group as the arbitrary cut-off point (<24 and >25 CAG repeats), the results show no association between the AR repeat length and schizophrenia in either sex. Furthermore. AR CAG repeat length did not affect the age of symptom onset in the schizophrenic population. Our findings suggest that it is unlikely that the AR CAG repeat polymorphism plays a major role in the pathogenesis of schizophrenia. Nevertheless, given that androgens affect cognitive function, violent behavior and mood, the effect of the AR CAG polymorphism on the clinical manifestations of schizophrenia may warrant further exploration.     

Analysis of a polymorphism in the tuberous sclerosis (TSC2) gene does not predispose to schizophrenia

The tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of malformations in various organs including the brain. A polymorphism in the TSC2 gene has been found to be increased in gangliogliomas, a lesion which is associated with disturbed neuro-glial cell migration pattern. Since these pathomorphological changes are compatible with disturbed neuronal migration in schizophrenic brains, we investigated this polymorphism in 130 families with a schizophrenic index patient. A 222-bp fragment of genomic DNA containing the TSC2 variant was analyzed by SSCP. The analysis revealed that there is no association with schizophrenia. Received: 16 April 1998 / Accepted: 13 October 1998     

Association between tryptophan hydroxylase gene polymorphism (A218C) and schizophrenic disorders

The human tryptophan hydroxylase (TPH) gene, the rate-limiting enzyme in serotonin biosynthesis, was localized on human chromosome 11p14-p15.3. Variation within intron 7 of the TPH gene was found to influence serotonin metabolism in the brain. To explore the possible role of TPH in the pathogenesis of schizophrenic disorders, we genotyped the TPH A218C polymorphism in 196 schizophrenic patients and 251 controls. The results demonstrated that genotype distribution was significantly different between schizophrenic patients and control subjects (P=0.002). No association was found between TPH genotypes and suicidal history in schizophrenic patients (P=0.239). The positive finding in this study suggests that the TPH 218A allele is a risk factor for schizophrenic disorders or is in linkage disequilibrium with the putative schizophrenia susceptibility locus in Han Chinese population.     

No significant association between the genetic polymorphisms in the GSK-3 beta gene and schizophrenia in the Chinese population

The GSK-3 beta gene encodes a protein kinase which is abundant in the brain, and its product is involved in signal transduction cascades of neuronal cell development, energy metabolism and body pattern formation. Previous studies have suggested that GSK-3 beta might act as a potential candidate locus for schizophrenia susceptibility. We genotyped six SNPs within the gene and conducted a case-control study involving 329 schizophrenic patients and 288 healthy subjects in the Chinese population. We examined allele and genotype frequencies and haplotype distributions in the subtype of paranoid schizophrenic patients as well as schizophrenic subjects in general. Our results fail to replicate the association of the GSK-3 beta gene with susceptibility to schizophrenia in the Chinese population.     

5-羟色胺转运体基因多态性与精神分裂症的相关性研究

目的：探讨中国汉族人群中5一羟色胺转运体（5-HTT）基因与精神分裂症之间的相关性。方法：189例符合中国精神障碍分类与诊断标准第3版及美国精神障碍诊断与统计手册第4版精神分裂症诊断标准的患者（患者组）使用聚合酶链式反应扩增5-HTT基因的启动子区（5-HTrLPR）位点和内含子区（5-HTTVNTR）位点,以琼脂糖凝胶电泳分离法进行基因分型,并和300名正常人（正常对照组）进行对照。结果：患者组与正常对照组之间5-HTTLPR位点L／L、L／S和S／S基因型频率以及等位基因L、s频率分布上差异具有统计学意义（x2=47．882,x2=44．188;P〈0．01或P〈0．001）;5-HTTVNTR位点12／12、12／10、10／10基因型频率和等位基因10、12频率分布上差异无统计学意义（X2=0．335,X。=0．051;P均〉0．05）。结论：S／S基因型及S等位基因可能是精神分裂症患者的易感等位基因;5-HT．TVNTR位点在中国汉族人群精神分裂症发病机制中可能不起主要作用。     

Chromosome abnormalities, mental retardation and the search for genes in bipolar disorder and schizophrenia

Genetic factors contribute to schizophrenia and bipolar disorder, and linkage and association studies have been successful in identifying several candidate genes. However these genes explain only a very small part of the total population risk and the psychoses appear to be very heterogeneous with several models of genetic inheritance relevant to different groups of patients, including some cases caused by multiple common genetic variants, while others are single gene disorders. Studying chromosomal abnormalities is a useful strategy for identifying genes in illness, and patients with both mental retardation and psychosis form a special group where large chromosomal abnormalities detected by routine cytogenetic analysis are more prevalent than in patients with schizophrenia or bipolar disorder alone, or in the general population. Studying these patients provides valuable opportunities to identify genes contributing to psychoses. This review of the literature on large chromosomal rearrangements in patients with mental retardation and psychotic illness illustrates how schizophrenia and bipolar phenotypes are associated with a large number of different chromosomal disruptions. Recent genome wide association studies have identified an excess of small chromosomal deletions and duplications in schizophrenia, adding further support to the importance of chromosomal structural variation in psychotic illness. The genesGRIK4 andNPÄS3, each associated with psychosis in patients with mental retardation are discussed to illustrate the value of rare cytogenetic events as a means to signpost neurobiological pathways of general importance for illness in the wider population.     

精神分裂症患者5-HT2A受体基因相关因素的研究

目的　分析汉族人 5 HT2A受体基因与精神分裂症易感性之间的关系以及影响患者 5 HT2A受体基因的相关因素。方法　 2 6 9例精神分裂症病人 ,310例正常对照 ,用聚合酶链式反应 (PCR)扩增及限制性片段长度多态性 (RFLPs)技术测定其 5 HT2A受体基因型和等位基因。结果　发现含 5 HT2A受体基因的等位基因A2的精神分裂症患者平均发病年龄明显大于含等位基因A1的患者 ,但 5 HT2A受体基因与精神分裂症的易感性、患者的性别、家族史、症状严重度均无显著相关。结论　 5 HT2A受体基因的等位基因A2可明显推迟精神分裂症患者的发病年龄 ,但 5 HT2A受体基因不影响汉族人精神分裂症的易感性、患者的症状严重度 ,患者 5 HT2A受体基因的频率分布也不受患者的性别、家族聚集性的影响