No proof of linkage between schizophrenia-related disorders including schizophrenia and chromosome 2q21 region

Summary We examined linkage between schizophrenia and schizophrenia-related disorders and five genetic markers on chromosome 2 in fourteen families ascertained through affected probands in St. Louis and Vienna. The chromosomal region 2q21 was considered a candidate locus for schizophrenia because of a report of a balanced translocation 2;18 (q21;q23) in a schizophrenia family. Linkage analyses were conducted for three disease models: a narrow model including schizophrenia only; an intermediate model including a spectrum of schizophrenia-related disorders; and a broad model including major affective disorders. Multipoint linkage analyses excluded linkage across the region (about 50cM) for the intermediate disease model. The same was generally true for the broad affection status model. None of the two-point and multipoint analyses showed definite linkage of schizophrenia to any marker. The most prominent positive association was between D2S44 and a broad affection status model, giving a two-point lod score of 1.71 at 0.20 recombination fraction.     

Possible linkage of schizophrenia and bipolar affective disorder to chromosome 3q29: a follow-up

The present linkage study is a follow-up within the chromosome 3q29 region in schizophrenia and bipolar affective disorder families, based on our recently published genome scan, resulting in evidence for linkage of both disorders to this region (marker D3S1265: NPL [non parametric lod] score Z_all=3.74, P=0.003). Using the same family sample (five pedigrees with schizophrenic index patients and three pedigrees with index bipolar disorder patients N=86; 50 of them were available for genotyping), genotyping of eight additional markers close to D3S1265 was done. Five of those new markers (three centromeric and two telomeric of D3S1265) spanning 4.14 cM (centiMorgan) could be used for statistical analyses (“new markers”). Moreover, marker D3S1265, genotyped within the published genome scan, was used for additional calculations. Linkage analysis was performed using the GENEHUNTER program version 2.1r3. Within newly genotyped markers the highest NPL score Z_all observed was 1.93296 with the telomeric SNP (single nucleotide polymorphism) rs1835669, corresponding to P=0.032166. Statistical analysis including D3S1265, located in between the newly genotyped markers, resulted in a peak NPL score Z_all=4.00179 with marker D3S1265, that is P=0.000128. Doing subset analyses of the bipolar disorder and schizophrenia families separately with new markers and D3S1265, linkage signals arose substantially from bipolar disorder families, with contribution from schizophrenia families, too. The results of our follow-up study support our previous linkage finding of schizophrenia and bipolar affective disorder to chromosome 3q29.     

Mutation analysis of the zinc transporter gene SLC30A4 reveals no association with periodic catatonia on chromosome 15q15

Summary. The zinc transporter gene SLC30A4, located on chromosome 15q15-q21, has previously been reported to show altered expression patterns in post mortem analysis of the brains of schizophrenic patients. As a positional candidate we investigated SLC30A4 in the chromsome 15q15-linked schizophrenic phenotype periodic catatonia (MIM 605419), by means of a systematic mutation screening in affected individuals from exceptionally large pedigrees with perfect co-segregation of a chromosomal segment between marker D15S1042 and D15S659 in all affected individuals. The mutation scan revealed no genetic variants within the coding and the putative promoter region of SLC30A4 and, thus, excludes a genetic association of SLC30A4 with catatonic schizophrenia.Received January 30, 2003; accepted September 4, 2003     

Distribution of the B33 CTG repeat polymorphism in a subtype of schizophrenia

Clinical evidence for a dominant mode of inheritance and anticipation in periodic catatonia, a distinct subtype of schizophrenia, suggests that trinucleotide repeat expansions may be involved in the aetiology of this disorder. Since genes with triplet repeats are putative canditates for causing schizophrenia, we have analysed the polymorphic B33 CTG repeat locus on chromosome 3 in 45 patients with periodic catatonia and 43 control subjects. The B33 CTG repeat locus was highly polymorphic, but all alleles in both the patient and control groups had repeat lengths within the normal range. We conclude that susceptibility to periodic catatonia is not influenced by variation at the B33 CTG repeat locus. Nevertheless, that periodic catatonia displays dominant inheritance and anticipation, characteristic of genetic disorders involving trinucleotide repeats, justifies further screening for triplet repeat expansions in this illness. Received: 31 January 1997 / Accepted: 16 October 1997     

The human small conductance calcium-regulated potassium channel gene (hSKCa3) contains two CAG repeats in exon 1, is on chromosome 1q21.3, and shows a possible association with schizophrenia

Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. We have previously identified the human small conductance calcium-activated potassium channel gene ( hSKCa3 ) which has two tandemly arranged CAG repeats in its 5' region. Here we have isolated the first genomic clones containing the gene and have shown that both repeats are in exon 1 . Homology to the previously localized sequence tagged site G16005 indicated that the gene may be on chromosome 22q, however using polymerase chain reaction amplification of somatic cell hybrid DNA and fluorescence in situ hybridization of two P1 artificial chromosome clones, we physically localized the gene to chromosome 1q21.3. We previously found an association between the highly polymorphic second (more 3′) CAG repeat and schizophrenia in 98 patients and 117 controls. We have now genotyped an additional 19 patients with schizophrenia and have performed statistical analyses on the entire group of patients and controls to investigate the possible effect of age of onset, family history, and gender of the patients on the observed association. None of these factors were found to influence the results. Both CAG repeats have been typed in 86 bipolar I disorder patients, and no significant difference in allele distribution was observed between our bipolar disorder patients and controls. Received: February 16, 1998 / Accepted: April 24, 1998     

Triplet repeats in clinical subtypes of schizophrenia: variation at the DRPLA (B37 CAG repeat) locus is not associated with periodic catatonia

Summary Clinical evidence for a dominant mode of inheritance and anticipation in periodic catatonia, a distinct subtype of schizophrenia, indicates that genes with triplet repeat expansions or other unstable repetitive elements affecting gene expression may be involved in the etiology of this disorder. Because patients affected with dentatorubral-pallidoluysian atrophy (DRPLA) may present with schizophrenic symptoms, we have investigated the DRPLA (B 37 CAG repeat) locus on chromosome 12 in 41 patients with periodic catatonia. The B 37 CAG repeat locus was highly polymorphic but all alleles in both the patient and control group had repeat sizes within the normal range. We conclude that variation at the DRPLA locus is unlikely to be associated with periodic catatonia. The evidence for dominant inheritance and anticipation as well as the high prevalence of human brain genes containing trinucleotide repeats justifies further screening for triplet repeat expansions in periodic catatonia.     

山东半岛东部地区精神分裂症21号染色体基因扫描研究

目的用DNA混合池(DNA pooling)的方法,通过微卫星遗传标记对精神分裂症患者及对照者的21号染色体进行扫描,寻找精神分裂症的关联区域。方法在21号染色体上间隔10 cM(厘摩)遗传距离选择了5个微卫星遗传标记,对119例精神分裂症患者与119例正常对照者组成的DNA混合样本分别进行了扫描。用卡方[X~2]检验的方法进行统计学分析,逐一比较患者组与对照组等位基因峰型比率的差异。结果在D21S1256遗传位点患者组和对照组的等位基因频率差异有显著性意义,P＜0．001。结论山东半岛东部地区精神分裂症患者群体在21号染色体长臂存在关联区域,可能包含致病基因或调控因子的病变。     

神经营养素-3基因启动区多态与精神分裂症的连锁不平衡研究

目的 探讨神经营养素－３（ｎｅｕｒｏｔｒｏｐｈｉｎ－３,ＮＴ－３）基因启动区二核苷酸重复多态与精神分裂症之间的关系。方法 对１１５个精神分裂症患者家系「其中同胞家系（１０５个）及核心家系（１０个）」进行基因分型,并结合诊断、阳性与阴性症状量表（ＰＡＮＳＳ）４个分量表的评分及发病年龄进行多等位基因模型和二等位基因模型的连锁不平衡分析。结果 （１）在多等位基因模型的连锁不平稳分析中,全体家系及发病年龄     

Allelic variants in the zinc transporter-3 gene,SLC30A3, a candidate gene identified from gene expression studies,show gender-specific association with schizophrenia

Previous microarray analysis of gene expression in frontal cortex showed differential expression of genes associated with synaptic function in schizophrenia compared to matched-controls in two independent cohorts. One of these genes validated in both cohorts, SLC30A3, which encodes the Zinc Transporter 3 (ZNT3), is localised to synaptic vesicles in glutamate synapses and known to be involved in cognitive function. In view of the robust depletion of SLC30A3 mRNA in two independent studies and the importance of this gene in cognitive function, we investigated whether single nucleotide polymorphism (SNP) associations with schizophrenia could be detected in a UK case controlled schizophrenia cohort. Four SNPs were selected across this gene and genotyped in a cohort of cases and controls from East UK. We found significant associations with schizophrenia at the allelic (ORs: 1.51 to 1.57), genotype (ORs: 1.46 to 1.53) and haplotype level (P = 2.15 × 10⁻⁴). These associations proved to be gender-specific with significant effects of allele (ORs: 1.74 to 2.11), genotype (ORs: 1.78 to 2.14) and haplotype (P = 3.51 × 10⁻⁵) observed in female schizophrenia cases but not males, when split by gender. In conclusion, SNPs in SLC30A3 showed a gender-specific association with schizophrenia in this East UK cohort, which merits further investigation in other population samples.     

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 study of a (TG)n dinucleotide repeat at chromosome 15q13.3 and schizophrenia in the Chinese population

Linkage studies have suggested that chromosome 15q13–q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (TG)n dinucleotide repeat polymorphism at D15S976 and schizophrenia was investigated using two independent samples from the Han Chinese population. In a population-based study, no significant difference was found between the genotype and allele frequency distributions in schizophrenia patients and control subjects. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Further analysis of the parent-of-origin effect found nominally significant allele-wise transmission disequilibrium through maternal transmissions, while 157bp and 159bp alleles showed significant individual allelic transmission disequilibrium from heterozygous mothers to affected offspring. Our results did not support the hypothesis that the (TG)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility in the Chinese population. Further studies are needed to elucidate the putative parent-of-origin effect and its role in schizophrenia susceptibility.     

Susceptibility for schizophrenia is not influenced by a functional insertion/deletion variant in the promoter of the serotonin transporter gene

A possible dysregulation of serotonergic neurotransmission has been implicated in the aetiology of schizophrenic psychoses. In the present study we analysed allelic and genotypic variations of a recently described functional polymorphic region in the promoter of the human serotonin transporter gene (5-HTTLPR) and a variable tandem repeat (VNTR) in intron 2 of the 5-HTT gene. We investigated 413 unrelated individuals, 180 schizophrenic patients and 233 blood donors as controls. With regard to the 5-HTTLPR, both the schizophrenic and the control group did not significantly differ between genotype frequencies (χ², p = 0.920) and allele frequencies (χ², p = 0.836). The odds ratio for subjects with schizophrenia who were homozygous for the short allele was 1.04 (95% CI 0.59–1.84). No evidence of allelic association to specific schizophrenia subtypes was found. The 5-HTT associated VNTR also showed no significant differences between either the allelic or the genotypic distributions. Haplotype analysis revealed a significant overall linkage disequilibrium at a level of p = 0.00004. Our findings indicate that both polymorphisms are unlikely to play a substantial role in the genetic predisposition to schizophrenic disorders. Received: 14 April 1997 / Accepted: 16 October 1997     

Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.     

The Ser9Gly polymorphism of the dopamine D3 receptor gene and risk of schizophrenia: an association study and a large meta-analysis

Dopamine D3 receptor (DRD3) binds antipsychotic drugs and is abundant in the limbic system of the brain. It has been shown to play important roles in schizophrenia. A number of studies investigated the Ser9Gly polymorphism of the DRD3 gene to test its possible association with schizophrenia; however, the results were inconsistent. Our study aims to further evaluate the possible association between the Ser9Gly polymorphism and schizophrenia using a case-control association study within the Han Chinese population as well as a meta-analysis covering all previous studies. Our study, based on 329 schizophrenic patients and 288 controls, found no significant difference in the genotype or allele distributions of Ser9Gly polymorphism, the meta-analysis showed that the Ser9Gly polymorphism was not associated with Schizophrenia. Our study does not support the contention that the Ser9Gly polymorphism of the DRD3 gene plays a major role in schizophrenia in the Chinese population.     

Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form

Amyotrophic lateral sclerosis (ALS) is a conformational disease in which misfolding and aggregation of proteins such as SOD1 (familial ALS) and TDP-43 (sporadic ALS) are central features. The conformations adopted by such proteins within motor neurons in affected patients are not well known. We have developed a novel conformation-specific antibody (USOD) targeted against SOD1 residues 42–48 that specifically recognizes SOD1 in which the beta barrel is unfolded. Use of this antibody, in conjunction with the previously described SEDI antibody that recognizes the SOD1 dimer interface, allows a detailed investigation of the in vivo conformation of SOD1 at the residue-specific level. USOD and SEDI immunohistochemistry of spinal cord sections from ALS cases resulting from SOD1 mutations (A4V and ΔG27/P28) shows that inclusions within remaining motor neurons contain SOD1 with both an unfolded beta barrel and a disrupted dimer interface. Misfolded SOD1 can also be immunoprecipitated from spinal cord extracts of these cases using USOD. However, in ten cases of sporadic ALS, misfolded SOD1 is not detected by either immunohistochemistry or immunoprecipitation. Using the amyloid-specific dyes, Congo Red and Thioflavin S, we find that SOD1-positive inclusions in familial ALS, as well as TDP-43- and ubiquitin-positive inclusions in sporadic ALS, contain non-amyloid protein deposits. We conclude that SOD1 misfolding is not a feature of sporadic ALS, and that both SOD1-ALS and sporadic ALS, rather than being amyloid diseases, are conformational diseases that involve amorphous aggregation of misfolded protein. This knowledge will provide new insights into subcellular events that cause misfolding, aggregation and toxicity.     

Facioscapulohumeral muscular dystrophy gene in Dutch families is not linked to markers for familial adenomatous polyposis on the long arm of chromosome 5

Cosegregation of facioscapulohumeral muscular dystrophy (FSHD) and familial adenomatous polyposis (FAP) has been described in two small families. The gene for FAP is located on the long arm of chromosome 5. We studied two large Dutch families with FSHD and found no evidence for linkage with gene markers closely linked to FAP. These results strongly suggest that the FSHD gene segregating in the Dutch families is not localized close to the FAP locus on chromosome 5.