X Liu

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.

Association of DAAO with schizophrenia in the Chinese population.

Recently, the gene called DAAO was reported to be associated with schizophrenia in the French Canadian populations. Here, we report a result obtained in the study of our large collection of 547 schizophrenia cases and 536 controls in the Chinese population. Six single-nucleotide polymorphisms (SNPs) were genotyped at and around the DAAO locus, covering a 10-kb region entirely encompassing the complementary DNA sequences of DAAO. We found statistically significant differences in allele distributions on one marker: SNP rs3741775 (P = 0.0000001). In the haplotype analysis based on the information of linkage-disequilibrium block across this gene locus, we demonstrated a highly significant association between schizophrenia and a DAAO haplotype (P = 2.0173 x 10(-21)), which therefore provides an independent statistical support for association of the DAAO gene with schizophrenia and indicates that the DAAO gene may play a significant role in the etiology of schizophrenia in the Han Chinese.

No association between (AAT)(n) repeats in the cannabinoid receptor gene (CNR1) and heroin abuse in a Chinese population

No association between (AAT) n repeats in the cannabinoid receptor gene (CNR1) and heroin abuse in a Chinese population

Family-based association study of synapsin II and schizophrenia.

Synapsin II has been proposed as a candidate gene for vulnerability to schizophrenia on the basis of its function and its location in a region of the genome implicated by linkage studies in families with schizophrenia. We recently reported positive association of synapsin II with schizophrenia in a case-control study (Chen et al. 2004). However, since case-control analyses can generate false-positive results in the presence of minor degrees of population stratification, we have performed a replication study in 366 additional Han Chinese probands and their parents by use of analyses of transmission/disequilibrium for three in/del markers and three single-nucleotide polymorphisms. Positive association was observed for rs2307981 (P =.02), rs2308169 (P =.005), rs308963 (P =.002), rs795009 (P =.02), and rs2307973 (P =.02). For transmission of six-marker haplotypes, the global P value was.0000016 (5 degrees of freedom), principally because of overtransmission of the most common haplotype, CAA/-/G/T/C/- (frequency 53.6%; chi (2) = 20.8; P =.0000051). This confirms our previous study and provides further support for the role of synapsin II variants in susceptibility to schizophrenia.

Possible association of the MAG locus with schizophrenia in a Chinese Han cohort of family trios

Neurotransmitter-based hypotheses have so far led to only moderate success in predicting new pathogenetic findings in etiology of schizophrenia. On the other hand, the more recent oligodendroglia hypotheses of this disorder have been supported by an increasing body of evidence. For example, the expression level of the myelin associated glycoprotein (MAG) gene has been shown to be significantly lower in schizophrenia patient groups compared to control groups. Such an effect might be a result of genetic variations of the MAG gene. In order to test this hypothesis, we genotyped four markers within the MAG locus in 413 trios sample of the Han Chinese using allele-specific PCR. None of the four markers revealed noticeable allelic significance. However, the four-marker and two-marker haplotypes covering components rs720309 and rs720308 were observed to be significantly associated with schizophrenia (P < 0.0001) in this study. In addition, we identified one common risk haplotype TA (rs720309-rs720308, present in 78.5% of the general population) that showed increased evidence of overtransmission from parents to affected offspring (P = 0.0001). The results demonstrated MAG might play a role in genetic susceptibility to schizophrenia. Furthermore, our finding of a possible association between the MAG locus and schizophrenia is in agreement with the hypotheses of oligodendrltic and myelination dysfunction.

A family-based association study of the MOG gene with schizophrenia in the Chinese population.

Recently the expression of human myelin/oligodendrocyte glycoprotein (MOG) has been found to be significantly downregulated in the brain tissue of subjects with schizophrenia, suggesting that the MOG gene resides within a high-susceptibility locus for schizophrenia. In order to test this prediction, we analyzed three microsatellites from MOG in the Han Chinese population using a sample of 532 trios. Analysis of allele, genotype and haplotype frequencies showed weak positive association between the markers and the disease (p=0.01982). Our results would indicate that the MOG gene may play a significant role in schizophrenia in the Han Chinese. However, further study is required using other methods and involving other populations.

MPZL1/PZR, a novel candidate predisposing schizophrenia in Han Chinese

The MPZL1/PZR gene has been mapped to 1q23.3, located in close proximity to a recognized schizophrenia susceptibility locus. Recently, the MPZL1/PZR gene has been found to be significantly upregulated in schizophrenia brain tissue and to play an important role in cell signaling, thus indicating that MPZL1/PZR could be a potential schizophrenia marker. To test this hypothesis, we selected three single nucleotide polymorphisms (SNPs) for genotyping in 523 Han Chinese trios. We found that two individual SNPs were significant at the Bonferronis corrected significance level P<0.017: rs3767444 (χ2=6.299, P=0.0121) and rs2051656 (χ2=9.856, P=0.0017). Haplotype transmission/disequilibrium tests revealed a significant association with the disease (global P-value=1.064 × 10−6), but no specific transmission distortions. Thus, we propose that the MPZL1/PZR gene may be important in the predisposition to schizophrenia among Han Chinese.

No evidence of linkage disequilibrium between a CAG repeat in the SCA1 gene and schizophrenia in Caucasian and Chinese schizophrenic subjects.

Several recent studies have reported evidence for a schizophrenia locus on chromosome 6p, with a variety of linked markers spanning a approximately 40 cM region between D6S470 and D6S291. However because of the wide region implicated and the difficulty of inferring phenotype from genotype in complex disorders, it is difficult to define its location precisely using linkage data. An alternative approach is to search for linkage disequilibrium. On chromosome 6p, allelic association with a (CAG)29 allele of a triplet repeat marker in the SCA1 gene has been reported, and we have attempted to replicate this finding using a Caucasian case-control sample of 211 affected subjects and 204 controls, and a Han Chinese sample of 100 affected family trios. In the case-control sample, the frequency of the (CAG)29 allele was similar in cases and controls (35%), and no other alleles provided evidence for allelic association. Likewise, there was no evidence for preferential transmission of the (CAG)29 allele to affected offspring in the Chinese sample, although a different allele, (CAG)26, was more often transmitted to the affected offspring. However this data did not reach statistical significance (P = 0.1). We conclude that our data does not support the notion that there is a locus for schizophrenia close to the SCA1 gene. However, since linkage disequilibrium will vary between distinct populations, we cannot exclude this possibility.