Dissecting the genetic complexity of schizophrenia

Karayiorgou, Maria; Gogos, Joseph A.

doi:10.1038/sj.mp.4000271

Cited by 50 publications

(27 citation statements)

References 24 publications

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“…[16][17][18] There is also suggestive evidence for linkage of both schizophrenia and bipolar disorder to chromosome 22q (reviewed in Karayiourgou and Gogos 19 ; see also [20][21][22][23] ). Early studies on biochemical markers for schizophrenia reported higher COMT activity in patients compared to controls (reviewed in Baron et al 24 ), but these results were not conclusive.…”

Section: Introductionmentioning

confidence: 99%

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

Ball

Zhao³

et al. 2000

Mol Psychiatry

126

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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.

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Section: Introductionmentioning

confidence: 99%

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

Ball

Zhao³

et al. 2000

Mol Psychiatry

126

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“…[12][13][14][15] Many regions now have support from multiple independent studies, although due to major methodological differences between studies, the cumulative strength of the evidence for each locus remains difficult to judge. Recent reviews, [16][17][18][19][20] when taken together, provide a fairly comprehensive catalog of the most positive studies, but it is likely that negative results are substantially under-represented in the literature. At the moment, the following ten regions are, arguably, those most deserving of higher density mapping and follow-up studies: 1q21-22, 19 67 and Xp11.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

et al. 2002

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From our linkage study of Irish families with a high density of schizophrenia, we have previously reported evidence for susceptibility genes in regions 5q21-31, 6p24-21, 8p22-21, and 10p15-p11. In this report, we describe the cumulative results from independent genome scans of three a priori random subsets of 90 families each, and from multipoint analysis of all 270 families in ten regions. Of these ten regions, three (13q32, 18p11-q11, and 18q22-23) did not generate scores above the empirical baseline pairwise scan results, and one (6q13-26) generated a weak signal. Six other regions produced more positive pairwise and multipoint results. They showed the following maximum multipoint H-LOD (heterogeneity LOD) and NPL scores: 2p14-13: 0.89 (P = 0.06) and 2.08 (P = 0.02), 4q24-32: 1.84 (P = 0.007) and 1.67 (P = 0.03), 5q21-31: 2.88 (P = 0.0007), and 2.65 (P = 0.002), 6p25-24: 2.13 (P = 0.005) and 3.59 (P = 0.0005), 6p23: 2.42 (P = 0.001) and 3.07 (P = 0.001), 8p22-21: 1.57 (P = 0.01) and 2.56 (P = 0.005), 10p15-11: 2.04 (P = 0.005) and 1.78 (P = 0.03). The degree of 'internal replication' across subsets differed, with 5q, 6p, and 8p being most consistent and 2p and 10p being least consistent. On 6p, the data suggested the presence of two susceptibility genes, in 6p25-24 and 6p23-22. Very few families were positive on more than one region, and little correlation between regions was evident, suggesting substantial locus heterogeneity. The levels of statistical significance were modest, as expected from loci contributing to complex traits. However, our internal replications, when considered along with the positive results obtained in multiple other samples, suggests that most of these six regions are likely to contain genes that influence liability to schizophrenia.

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“…The reasons for contradictory results on the association of DRD2 gene with schizophrenia could be explained by the usage of unsuitable DNA markers, the widely variable frequency of A1 allele among different ethnic groups [Barr and Kidd, 1993], and the complexity and phenotypic heterogeneity of schizophrenia [Karayiorgou and Gogos, 1997]. There is, however, growing evidence that molecular heterosis and gender difference in the genetic effect at a certain loci may be additional reasons for such inconsistencies [Asherson et al, 1996;Thompson et al, 1997;Comings, 1999].…”

Section: Introductionmentioning

confidence: 99%

Gender‐specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia

et al. 2002

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We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n ¼ 66), the male counterpart (n ¼ 101) showed significant differences in their genotype distributions. The comparison between male smoking and nonsmoking patients showed the difference in genotype distribution (P ¼ 0.010) with a higher prevalence of A1 allele (P ¼ 0.020) and frequency of heterozygotes (P ¼ 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P ¼ 0.001), genotype distribution (P ¼ 0.00011), and frequency of heterozygotes (P ¼ 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies.

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Dissecting the genetic complexity of schizophrenia

Cited by 50 publications

References 24 publications

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 marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

Gender‐specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia

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