Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases.Molecular Psychiatry (2004) 9, 213-218. doi:10.1038/sj.mp.4001418 Published online 30 December 2003     

Lack of linkage to chromosome 5q11-q13 markers in six schizophrenia pedigrees

We examined linkage between schizophrenia and five genetic markers on chromosome 5 in six pedigrees. Analyses were run considering the affected phenotype to be schizophrenia, schizophrenia plus a spectrum of related disorders, and these disorders plus any axis I diagnosis. None of the analyses were suggestive of linkage at any of the markers, either considering the pedigrees individually or in the aggregate. In our pedigrees, multipoint linkage analyses excluded much of the region that had supported linkage in an earlier study. These findings are consistent with other attempts to replicate the chromosome 5 linkage finding.     

精神分裂症与5-羟色胺受体2A多态性相关性研究

目的 探测精神分裂症与5-HT2A受体基因多态性关系。方法用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术分析90例精神分裂症患者的5-HT2A受体（T102C）基因多态性,并以90例正常人作为对照。结果 在精神分裂症组和正常对照组中,等住基因A1、A2及基因型A1／A1、A1／A2、A2／A2的差异没有显著性（P〉0．05）。结论 本组样本中5-HT2A受体（T102C）基因多态性与精神分裂症无相关性。提示5-HT2A受体基因（T102C）突变可能不是导致精神分裂症发病的主要因素。     

精神分裂症与Xp11区HSU93305基因座的单体型及22 q11～13区相关基因的关联性研究

目的探讨Xp11区HSU93305基因座单体型、22 q11～13区α2肾上腺素能受体(A2αR)基因和儿茶酚-氧-甲基转移酶(COMT)基因多态性与精神分裂症的关联.方法分别提取59个中国汉族核心家系成员(母59名,父56名,精神分裂症患者59例)的DNA,采用基因扩增和限制性片段长度多态性技术,进行HSU93305基因座的单体型研究;选择其中56个父母均存活的家系进行A2αR基因和COMT基因多态性传递不平衡检验(TDT)的研究,并应用复等位基因TDT、基于单体型的单体型相对风险率(HHRR)检验等.结果 (1)Xp11区HSU93305基因座经Msp Ⅰ及Dra Ⅱ酶切后产生四种单体型D1M1,D1M2,D2M1,D2M2.父母组以单体型D2M1频率最高(57.7%);患者组也以D2M1传递率最高(59.0%),其次为D1M2(28.9%),D2M2传递率最低(1.2%).(2)经复等位基因TDT分析,精神分裂症与Xp11区HSU93305基因座相关联(χ2=9.28,v=3,P<0.05);与A2αR基因(χ2=1.09,v=1,P>0.05)和COMT基因(χ2=0.31,v=1,P>0.05)未见关联.(3)经HHRR检验,A2αR基因(χ2=1.21,v=1,P>0.05)和COMT基因(χ2=0.37,v=1,P>0.05)与精神分裂症亦未见关联.结论精神分裂症与HSU93305基因座相关联,其易感基因可能位于Xp11区;与A2αR基因和COMT基因多态性可能无关.     

Association between the CCR5 32-bp deletion allele and late onset of schizophrenia

OBJECTIVE: The 32-bp deletion allele in chemokine receptor CCR5 has been associated with several immune-mediated diseases and might be implicated in schizophrenia as well. METHOD: The authors genotyped DNA samples from 268 schizophrenia patients and 323 healthy subjects. Age at first admission to a psychiatric hospital department served as a measure of disease onset. RESULTS: Patients and comparison subjects differed marginally in their genotype distribution, with a slightly higher frequency of the deletion allele seen in the patients. The authors found the deletion allele to be associated with higher age at first admission. After age at first admission was analyzed as a continuous variable, it was dichotomized using 40 years as the cutoff. With this approach the authors found that genotype distributions of patients with age at first admission above the cutoff (possible cases of late-onset schizophrenia) and healthy subjects differed significantly. This was reflected in an increased frequency of the deletion allele in the patient subgroup. Patients with ages at first admission below and above 40 years significantly differed in distribution of genotypes and alleles, with an overrepresentation of the deletion allele in the latter subgroup of patients. CONCLUSIONS: These findings suggest that the CCR5 32-bp deletion allele is a susceptibility factor for schizophrenia with late onset. Alternatively, the CCR5 32-bp deletion allele may act as a modifier by delaying the onset of schizophrenia without affecting the disease susceptibility.     

Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14q21 and 17q11-12

Bipolar disorder (BP) is a severe and common psychiatric disorder characterized by extreme mood swings. Family, twin and adoption studies strongly support a genetic component. The mode of inheritance is complex and likely involves multiple, as yet unidentified genes. To identify susceptibility loci, we conducted a genome-wide scan with 343 microsatellite markers in one of the largest, well-characterized pedigree samples assembled to date (373 individuals in 40 pedigrees). To increase power to detect linkage, scan statistics were used to examine the logarithm of odds (lod) scores based on evidence at adjacent chromosomal loci. This analysis yielded significant evidence of linkage (genome-wide P&<0.05) for markers on 2p13-16. Standard linkage analysis was also supportive of linkage to 2p13-16 (lod=3.20), and identified several other interesting regions: 4q31 (lod=3.16), 7q34 (lod=2.78), 8q13 (lod=2.06), 9q31 (lod=2.07), 10q24 (lod=2.79), 13q32 (lod=2.2), 14q21 (lod=2.36) and 17q11-12 (lod=2.75). In this systematic, large-scale study, we identified novel putative loci for BP (on 2p13-16, 8q13 and 14q21) and found support for previously proposed loci (on 4q31, 7q34, 9q31, 10q21-24, 13q32 and 17q11-12). Two of the regions implicated in our study, 2p13-14 and 13q32, have also been linked to schizophrenia, suggesting that the two disorders may have susceptibility genes in common.     

Association study of a new schizophrenia susceptibility locus of 10q24.32-33 in a Han Chinese population

Recently, a new schizophrenia susceptibility locus 10q24.32-q24.33, containing two single-nucleotide polymorphisms (SNPs: rs7914558 and rs11191580), was identified in a genome-wide association study. To examine if this locus is associated with schizophrenia in the Han Chinese population, we analyzed six SNPs, including two SNPs within the region of interest. The sample consisted of 1430 schizophrenia cases and 1570 controls from genetically independent members of the Han population. Single-SNP association, haplotype association and sex-specific association analyses were performed. Three SNPs, rs7914558 (p=1.41×10(-4); OR=1.11; 95% CI 1.05-1.17), rs12220375 (p=1.18×10(-4); OR=1.06; 95% CI 1.03-1.09) and rs11191580 (p=3.03×10(-4); OR=1.05; 95% CI 1.02-1.10), mapped to the locus and were significantly associated in our sample set. Further genotype and haplotype association analyses suggested a similar pattern. Similar to results from European populations, our results provide further evidence that this region associated with schizophrenia in Han Chinese. Results also confirm previous reports suggesting that 10q24.32-q24.33 offers an intriguing new insight into the pathogenesis of schizophrenia and may play an important role in its etiology.     

Mutation screening and LD mapping in the VCFS deleted region of chromosome 22q11 in schizophrenia using a novel DNA pooling approach

We examined whether variation within six genes from the VCFS critical region at 22q11 (DGSC, Stk22A1, DGSI, Gscl, Slc25A1 and Znf74) confers susceptibility to schizophrenia. We screened the exons and flanking intronic sequence of each gene for mutations in 14 individuals with DSM-IV schizophrenia using DHPLC. All polymorphisms identified were characterised and genotyped in a sample of 184 schizophrenics and matched controls, using novel DNA pooling methods. Of the polymorphisms identified, 17 were located within exons, six were within coding sequence, and two were non-synonymous. Pooled genotyping revealed no differences in the allele frequencies for any polymorphism between cases and controls that met our pre-defined criterion (P < or = 0.1). In a complementary approach we also attempted to define the location of a schizophrenia susceptibility locus more precisely by performing association mapping using seven microsatellites spanning the VCFS region with an average inter-marker distance of 450 kb. Conventional chi(2) analysis of genotypes in 368 cases and 368 controls revealed that none of the markers was significantly associated (P < 0.05) with schizophrenia. However, evidence for significant association (P = 0.003) was obtained for D22S944 when alleles were combined. TDT analysis of D22S944 genotyped in a further 278 cases of schizophrenia and their parents failed to find any overall allele-wise significant transmission disequilibrium (chi(2) = 18.3, P = 0.17). However, individual analysis of the alleles revealed that allele 12 was excessively non-transmitted and that this almost reached significance when corrected for multiple alleles (chi(2) = 7.35, P = 0.006, P = 0.078 corrected for 13 alleles).     

Evidence against linkage of schizophrenia to chromosome 5q11-q13 markers in systematically ascertained families.

Ten pedigrees systematically ascertained in Germany were tested for linkage to chromosome 5q11-q13. In order to replicate the previous report by Sherrington et al (1988), families with a bipolar family member were omitted from the lod score calculations, all diagnoses were based upon Research Diagnostic Criteria, and four different models of the affection status were calculated, including the model for which Sherrington et al calculated the highest lod scores. None of the families investigated showed a positive lod score. Using multipoint linkage analyses, we were able to exclude the region for which a positive linkage has been reported.     

Failure to replicate linkage between chromosome 5q11-q13 markers and schizophrenia in 28 families.

Sherrington et al. (1988) reported linkage between markers located on the 5q11-q13 region of chromosome 5 and schizophrenia in five Icelandic and two British families. To date, however, all attempts to replicate the initial finding have failed. Using three markers of chromosome 5, we have studied 28 additional French pedigrees. When our data were analyzed both with parametric (i.e., lod scores) and nonparametric methods, we found no evidence of linkage. Thus, we were unable to replicate the earlier report by Sherrington et al.     

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     

Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11

Mol Psychiatry 2000; 5: 77-84     

Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11

Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84.     

A genome-wide association study in 574 schizophrenia trios using DNA pooling

The cost of genome-wide association (GWA) studies can be prohibitively high when large samples are genotyped. We conducted a GWA study on schizophrenia (SZ) and to reduce the cost, we used DNA pooling. We used a parent-offspring trios design to avoid the potential problems of population stratification. We constructed pools from 605 unaffected controls, 574 SZ patients and a third pool from all the parents of the patients. We hybridized each pool eight times on Illumina HumanHap550 arrays. We estimated the allele frequencies of each pool from the averaged intensities of the arrays. The significance level of results in the trios sample was estimated on the basis of the allele frequencies in cases and non-transmitted pseudocontrols, taking into account the technical variability of the data. We selected the highest ranked SNPs for individual genotyping, after excluding poorly performing SNPs and those that showed a trend in the opposite direction in the control pool. We genotyped 63 SNPs in 574 trios and analysed the results with the transmission disequilibrium test. Forty of those were significant at P<0.05, with the best result at P=1.2 x 10(-6) for rs11064768. This SNP is within the gene CCDC60, a coiled-coil domain gene. The third best SNP (P=0.00016) is rs893703, within RBP1, a candidate gene for schizophrenia.     

A genetic linkage study of schizophrenia to chromosome 5 markers in a northern Italian population.

Some recent findings report that the area 5q11.2-13.3 of chromosome 5 segregates with schizophrenia in an uncle-nephew pair (Bassett et al 1988). However, linkage studies between chromosome 5 markers loci and schizophrenia lead to different results: Sherrington et al (1988) found a positive linkage, whereas other groups of researchers found evidence against linkage (Kennedy et al 1988; St. Clair et al 1989; Detera-Wadleigh et al 1989; McGuffin et al 1990; Aschauer et al 1990; Crowe et al 1991). We have studied five Italian pedigrees segregating schizophrenia using a map of four markers for the chromosomal region 5q11.2-13.3. Linkage analyses revealed negative lod scores, and thus no evidence for linkage was obtained in our Italian families.     

Mutation screening and imprinting analysis of four candidate genes for autism in the 7q32 region

Genetic studies indicate that chromosome 7q is likely to contain an autism susceptibility locus (AUTS1). We have followed a positional candidate gene approach to identify the relevant gene and report the analysis of four adjacent genes localised to a 800 kb region in 7q32 that contains an imprinted domain: PEG1/MEST, COPG2, CPA1 and CPA5-a previously uncharacterised member of the carboxypeptidase gene family. Screening these genes for DNA changes and association analysis using intragenic single nucleotide polymorphisms (SNPs) provided no evidence for an etiological role in IMGSAC families. We also searched for imprinting mutations potentially implicated in autism: analysis of both DNA methylation and replication timing indicated a normal imprinting regulation of the PEG1/COPG2 domain in blood lymphocytes of all patients tested. The analysis of these four genes strongly suggests that they do not play a major role in autism aetiology, and delineates our strategy to screen additional candidate genes in the AUTS1 locus.