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

Li, T; Ball, David; Zhao, Jinghua; Murray, Robin M.; Liu, X; Sham, Pak C.; Collier, David

doi:10.1038/sj.mp.4000638

Cited by 126 publications

(104 citation statements)

References 42 publications

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“…For the present analysis minimum haplotype frequencies were set at 0.03 and ambiguity set at 3, ie haplotypes which occurred with a frequency of less than 3% were excluded and if there are more than three possible parental haplotypes the family was excluded. 10 …”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Consistent with this notion, several [although not all (Semwal et al, 2001)] studies using the family-based transmission disequilibrium test have shown the high-activity Val allele of COMT, which presumably increases dopamine catabolism, to be preferentially transmitted to schizophrenic offspring Kunugi et al, 1997;Li et al, 2000Li et al, , 1996. Interestingly, this Val 108/158 Met functional polymorphism has been reported to be associated with schizotypal personality traits even in healthy individuals, and in the same direction as observed in schizophrenic patients, that is, increased Val allele frequency (Avramopoulos et al, 2002).…”

Section: Introductionmentioning

confidence: 95%

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Matsumoto

Weickert

Beltaifa

et al. 2003

Neuropsychopharmacol

126

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Human prefrontal cortical neurons express catechol O-methyltransferase (COMT), an enzyme that inactivates the neurotransmitter dopamine. A functional polymorphism of COMT, Val 108/158 Met, affects prefrontal function, and the high-activity Val allele has been reported to be a genetic risk factor for schizophrenia. We used in situ hybridization histochemistry to measure mRNA levels of COMT in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia (N ¼ 14) and of normal controls (N ¼ 15). While the groups did not differ in terms of mean level of COMT mRNA, there was a significantly different laminar pattern of COMT mRNA expression in pyramidal neurons (F ¼ 2.68, df ¼ 4,108, Po0.04); patients with schizophrenia had relatively lower levels in the superficial (II/III) layers and higher levels in the intermediate/deep (IV/V) layers (Po0.01), while in controls, the expression was homogeneous across layers. Neither the mean level nor the laminar distribution of COMT mRNA was related to the Val 108/158 Met genotype, suggesting that the feedback regulation of mRNA level is not a compensation for the functional effect of the COMT polymorphism. The disease-related laminar difference of COMT expression may be involved in dysregulation of dopamine signaling circuits in the DLPFC of patients with schizophrenia.

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“…5,6 More importantly, genetic associations to genes in these linkage regions have been confirmed recently in multiple samples. [7][8][9] These genes include, among others, DISC1 on 1q, [10][11][12] DTNBP1 (dysbindin) on 6p, 13,14 NRG1 on 8p, 15 catechol-O-methyltransferase (COMT) on 22q, 16,17 DAOA (G72) on 13q 18,19 and RGS4 on 1q. [20][21][22] The linkage findings represented an important step, enabling targeted searches within defined regions of the genome.…”

Section: Introductionmentioning

confidence: 99%

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

et al. 2007

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Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD 67 ), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 5 0 flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 5 0 untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function.

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

Cited by 126 publications

References 42 publications

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

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

Catechol O-Methyltransferase (COMT) mRNA Expression in the Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression

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