Linkage and associated studies of schizophrenia

Riley, Brien P.; McGuffin, Peter

doi:10.1002/(sici)1096-8628(200021)97:1<23::aid-ajmg5>3.0.co;2-k

Cited by 161 publications

(102 citation statements)

References 183 publications

(143 reference statements)

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“…Nonetheless, there have been reports of linkage between schizophrenia and genetic markers on 14 different chromosomes (1, 2, 4, 5, 6, 7, 8, 9, 10, 13, 15, 18, 22 and X), covering thousands of genes. 24 Although, it is difficult to separate true positive findings from noise, the strongest evidence pointed to involvement of chromosomes 8p, 13q and 22q from meta-analysis of genome linkage studies. 25,26 These findings are in agreement with our genomic mapping of schizophrenia susceptibility loci (Figure 1), especially chromosome 22 being one of the most vulnerable chromosomes based on the integrated results of literature-based association studies (Table 1).…”

Section: Discussionmentioning

confidence: 99%

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Chu

Liu

2010

J Hum Genet

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Schizophrenia is a highly complex inheritable disease characterized by numerous genetic susceptibility elements, each contributing a modest increase in risk for the disease. Although numerous linkage or association studies have identified a large set of schizophrenia-associated loci, many are controversial. In addition, only a small portion of these loci overlaps with the large cumulative pool of genes that have shown changes of expression in schizophrenia. Here, we applied a genomic gene-function approach to identify susceptibility loci that show direct effect on gene expression, leading to functional abnormalities in schizophrenia. We carried out an integrated analysis by cross-examination of the literature-based susceptibility loci with the schizophrenia-associated expression gene list obtained from our previous microarray study (Journal of Human Genetics (2009) 54: 665-75) using bioinformatic tools, followed by confirmation of gene expression changes using qPCR. We found nine genes (CHGB, SLC18A2, SLC25A27, ESD, C4A/C4B, TCP1, CHL1 and CTNNA2) demonstrate gene-function correlation involving: synapse and neurotransmission; energy metabolism and defense mechanisms; and molecular chaperone and cytoskeleton. Our findings further support the roles of these genes in genetic influence and functional consequences on the development of schizophrenia. It is interesting to note that four of the nine genes are located on chromosome 6, suggesting a special chromosomal vulnerability in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

Chu

Liu

2010

J Hum Genet

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“…4 Additionally, the 6p21-6p23 region has previously been implicated by linkage studies. 2 We have attempted to replicate the finding using two Han Chinese samples: (a) 544 cases and 621 controls; and (b) 327 trios. We analysed the five loci chosen by Wei and Hemmings and found negative results with both markers and haplotypes.…”

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confidence: 91%

“…2 Wei and Hemmings 1 found that Notch4 was strongly associated with schizophrenia in a sample of 80 British trios. They analysed three microsatellites and two SNPs in and around the gene (on 6p23) and found marker and haplotype associations.…”

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A family-based and case-control association study of the NOTCH4 gene and schizophrenia

Fan

Tang

et al. 2002

Mol Psychiatry

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Recently a strong positive association between schizophrenia and Notch4 has been reported. 1 Both individual markers and haplotypes showed association with the disease, with five markers (three microsatellites and two SNPs) being tested. In order to test this finding we genotyped these markers in the Han Chinese population using a sample of 544 cases and 621 controls as well as Ͼ300 trios. Analysis of allele, genotype and haplotype frequencies in both samples showed no association between the markers and the disease. Our results would indicate that a significant role for the Notch4 gene in schizophrenia can be ruled out in the Han Chinese. However, similar studies are necessary in the Caucasian population as linkage disequilibrium arrangements and founder effects may differ between these two populations. Molecular Psychiatry (2002) 7, 100-103. DOI: 10.1038/ sj/mp/4000945Schizophrenia is a severe and common complex illness with a large genetic component, however major common risk loci have yet to be found. 2 Wei and Hemmings 1 found that Notch4 was strongly associated with schizophrenia in a sample of 80 British trios. They analysed three microsatellites and two SNPs in and around the gene (on 6p23) and found marker and haplotype associations. The Notch gene family encodes large transmembrane receptors and may regulate embryonic cell migration, vascular morphogenesis and remodelling. 3 Evidence from neuropathology and epidemiology suggests a significant proportion of schizophrenia cases have neurodevelopmental aetiology. 4 Additionally, the 6p21-6p23 region has previously been implicated by linkage studies. 2 We have attempted to replicate the finding using two Han Chinese samples: (a) 544 cases and 621 controls; and (b) 327 trios. We analysed the five loci chosen by Wei and Hemmings and found negative results with both markers and haplotypes. The physical positions of the markers are shown in Figure 1.In our case-control analysis 544 schizophrenics were genotyped and compared with a set of 621 controls. Table 1 gives the marker genotype and allele frequencies. The allele and genotype frequencies were in Hardy-Weinburg disequilibrium and did not differ by sex, age or region of origin. Likewise, there was little evidence of an overall difference in distribution in allele or genotype frequencies between cases and controls. Only the fifth marker, which is a slightly unstable TTAT repeat, gave slightly positive P-values of 0.03 overall and 0.01 for female sex, before correction for multiple testing (at least 50 tests were performed). Some difficulty was encountered in analysing haplotype frequencies and associations due to the large number of possible haplotypes (Ͼ2000), individuals (Ͼ1000) and marker combinations to be analysed. However, using an experimental version of EH Plus called FPEH (supplied by J Zhao), we analysed the haplotype frequencies for all markers and found no differences overall (P = 0.39) or for different combinations (data not shown). Thus there was no evidence from this study to support the asso...

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“…Recent findings in psychiatric genetics have renewed enthusiasm. For SZ, the available evidence from published genome scans and recent review papers [7][8][9][10] supports converging chromosomic regions as including probable loci for susceptibility genes : 1q21-q22, 6p24-p22, 8p21, 10p15-p11, 13q32 and 22q11-q13 showed up as the most congruent across SZ studies. As regards BP, several scans and reviews of linkage studies 5,[10][11][12] also conclude to converging susceptibility regions, the most likely being in 4p16-p15, 12q23, 13q32, 16p, 18q12-q22, 21q22 and 22q11-q12.…”

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confidence: 92%

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

et al. 2004

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The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N ¼ 480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels Â 2 models of transmission Â 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score 44.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores 41.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects. Molecular Psychiatry (2005) 10, 486-499.

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Linkage and associated studies of schizophrenia

Cited by 161 publications

References 183 publications

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

An integrated genomic analysis of gene-function correlation on schizophrenia susceptibility genes

A family-based and case-control association study of the NOTCH4 gene and schizophrenia

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families

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