Zhenqi Wang

A review and Re-evaluation of an association between the NOTCH4 locus and schizophrenia

This work reviewed all the reports on the NOTCH4 gene in schizophrenia, which have been published since the gene was found to be associated with illness among a British population in 2000. The results from independent studies were inconsistent. Allelic heterogeneity, clinical diagnosis, ethnical backgrounds, and linkage disequilibrium (LD) structures in the human genome may be major reasons for poor replication. A couple of studies suggested that the NOTCH4 gene could play a role in a subgroup of the disease, such as early‐onset schizophrenia and negative symptoms. A single study revealed a weak association of the NOTCH4 gene with frontal lobe brain volumes and a strong association with frontal lobe cognitive performance. A meta‐analysis showed stronger evidence of the NOTCH4 association in family‐based studies than in case‐control studies. In a previous study, we found that rs520692, a single nucleotide polymorphism (SNP) at the NOTCH4 locus, was associated with schizophrenia in a Chinese population. In the present study, we applied a large sample size to re‐evaluate our initial findings and then confirmed the rs520692 association with illness. The pairwise measures did not show strong LD between paired SNPs although the SNPs tested are located within a 34‐kb region, suggesting that LD within the NOTCH4 gene has been broken rapidly by historical recombination in the Chinese population. Taken together, the NOTCH4 gene may be associated with schizophrenia but how the gene contributes to the etiology of the illness needs a further investigation.

A study of the PEMT gene in schizophrenia

The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X2=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X2=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X2=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X2=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.

A Family-and Population-Based Study of the UFD1L Gene for Schizophrenia

The present work was undertaken to investigate the association of the UFD1L locus with schizophrenia among 304 Chinese family trios of Han descent. We detected four single nucleotide polymorphisms (SNPs) in the 5′‐end region of the UFD1L gene. The transmission disequilibrium test (TDT) revealed allelic associations for rs5746744 (χ2 = 8.02, P = 0.005) and rs1547931 (χ2 = 7.18, P = 0.007), but failed to replicate disease association for rs5992403 present in the promoter region, which was initially found in Italian and Canadian samples. The allelic association for rs5746744 and rs1547931 was replicated with independently recruited case–control samples. The 2‐SNP haplotype analysis showed an association for the rs5992403‐rs5746744 haplotypes (χ2 = 18.92, df = 3, P = 0.0003), the rs5746744‐rs1547931 haplotypes (χ2 = 11.06, df = 3, P = 0.011) and the rs1547931‐rs2238769 haplotypes (χ2 = 18.88, df = 3, P = 0.0003). The 4‐SNP haplotype analysis also showed strong association with illness (χ2 = 29.54, df = 9, P = 0.0005) but there were more than one individual haplotypes with a low frequency excessively non‐transmitted. The four SNPs tested were not located in the same LD block among the Chinese population. This study raises the possibility that a disease‐resistant variant may be carried by two or more haplotypes at the UFD1L locus due to frequent recombination during meiosis.

Genetic and functional study of the IPO5 gene in schizophrenia

The present work reported on a weak association of the importin 5 (IPO5) gene with schizophrenia in combined family and case-control samples and also investigated a possible mechanism by which the IPO5 gene may contribute to the development of the disease in a Chinese population. Our results suggest that abnormal expression and alternative splicing of the IPO5 gene may be involved in the pathophysiology of schizophrenia.

Further study of genetic association between the TNXB locus and schizophrenia.

Correspondence to Xuan Zhang, MD, PhD, Research Center for Genomic Medicine and MH Radiobiology Research Unit, School of Public Health, Jilin University, Changchun 130021, China Tel: + 86 431 85619443; fax: + 86 431 85619151; e-mail: zhangxuan2010@yahoo.com.cn and Jiang Wu, MD, PhD, Research Centre for Neuroscience and Department of Neurology, Jilin University First Hospital, Changchun 130021, China Tel: + 86 431 88782764; fax: + 86 431 88782378; e-mail: sjnkwujiang@sina.com

A family-based study of genetic association of the PTGDS gene with schizophrenia in a Chinese population.

Several lines of evidence suggest that niacin-induced dermal flush may be a biomarker for schizophrenia (Ward et al., 1998; Puri et al., 2001; Liu et al., 2007). Up to 80% of schizophrenic patients show diminished niacin flush as compared with 20% of healthy individuals (Ward et al., 1998; Puri et al., 2001). As the niacin flush is highly inheritable (Waldo, 1999; Lin et al., 2007), the niacin skin test can be used as endophenotypes to track down a gene for schizophrenia. Many genes, however, are involved in the niacin flush pathway, including those for niacin receptors, phospholipase A2, prostaglandin synthases and receptors. The genes involved in the prostaglandin D2 (PGD2) pathway may be particularly important as niacin flush mainly reflects the PGD2-induced vasodilatation. In a recent study, Ruano et al., 2007 detected the PGD2 synthase (PTGDS) gene for genetic association with schizophrenia in Portuguese and Brazilian populations, but they failed to observe disease association. We have also recently tested the PTGDS gene for its association with the illness in a Chinese population. A total of 282 Chinese parent-offspring trios of Han descent were recruited for the genetic analysis. The patients (181 males and 101 females), aged 25.3 ± 6.7 years, were admitted to a psychiatric hospital in Northeast China during the period between 2000 and 2005. They were diagnosed as having schizophrenia using the ICD-10 (International Statistical Classification of Diseases and Related Health Problems: Tenth Revision) criteria. All the participants gave written informed consent for the genetic analysis as approved by the ethics committee of the Jilin University.

Lack of genetic association of the TGM2 gene with schizophrenia in a Chinese population

The gene coding for transglutaminase 2 (TGM2) has been reported to be associated with schizophrenia in a White population. The present study was then designed to replicate this initial finding in a Chinese population. A total of 428 individuals with schizophrenia and 555 control participants were recruited for genetic analysis. Four single nucleotide polymorphisms present in the TGM2 gene were selected for genotyping, including rs2076380, rs7270785, rs4811528, and rs6023526, by PCR-based restriction fragment length polymorphism analysis. None of these four single nucleotide polymorphisms genotyped showed an association with schizophrenia, although these 428 cases and 555 controls had 97% power to detect a disease association in small effect size (odds ratio=1.5). The present results did not support the TGM2 association with schizophrenia. It is thus possible that the TGM2 finding may have resulted from a random error of sampling.

Lack of genetic association between the MYO9B locus and schizophrenia in a Chinese population.

Jungerius et al. (2008) have reported that the myosin IXB (MYO9B) gene is strongly associated with susceptibility to schizophrenia in a Dutch population. However, this initial work failed to be replicated in a British population (Law et al., 2011). The present study was then undertaken to examine whether the association of MYO9B with schizophrenia could be replicated in a Chinese population.

No association between the HLA-DQB1*0501 variant and schizophrenia in a Chinese population.

Songlei Guan, Xuan Zhang, Qi Xu, Shilong Sun, Zhenqi Wang and Jun Wei, School of Public Health and MH Radiobiology Research Unit, Jilin University, School of Life Science, Jilin Agricultural University, Changchun, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China and The Genetics & Immunology Research Group, Centre for Health Science, Health Faculty, University of the Highlands and Islands, Inverness, UK

Investigation of the Interaction Between the Ser447Term Polymorphism of Lipoprotein Lipase and the Stroke-Related Risk Factors in Ischemic Stroke

The present study aimed to investigate the interaction between the Ser447Term polymorphism in the lipoprotein lipase (LPL) gene and some common risk factors for stroke. A total of 704 unrelated patients with ischemic stroke were recruited for genetic analysis; they were all of Han Chinese origin. These patients were classified into subgroups based on their exposure to stroke-related risk factors, including type 2 diabetes, hypertension, smoking, and hyperlipidemia. The Ser447Term polymorphism was genotyped by PCR-based restriction fragment length polymorphism analysis. The chi-square (χ2) test showed that the frequency of Ser447Term G allele was significantly higher in stroke patients with a history of diabetes than in those without a history of diabetes (χ2 = 7.25, P = 0.007, OR = 1.78, 95%CI 1.18–2.68). Allelic association was not observed in patients exposed to the other three stroke-related risk factors. The combined effect of the LPL gene polymorphisms and diabetes may contribute to the development of a subgroup of ischemic stroke.