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

Abstract

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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Association study between dopamine D3 receptor gene variant and personality traits

“…Even when highly significant results emerge, all subsequent replication attempts may fail. A recent example is the proposed association between the NOTCH4 gene and schizophrenia [Wei and Hemmings, 2000;Imai et al, 2001;McGinnis et al, 2001;Sklar et al, 2001;Ujike et al, 2001;Fan et al, 2002;Carmine et al, in press]. Considering the large number of potential genes and environmental influences involved in the genesis of personality and psychiatric disorders, false positive results are likely to appear.…”