Genetic Studies Of Schizophrenia And Brachydactyly Type A2

Schizophrenia is a common mental disease that affects approximately 1% of the world's population, with heritability estimates of around 80%. Understanding the etiology and pathogenesis of schizophrenia is one of the most important challenges facing psychiatry. However, identification of specific susceptibility genes for schizophrenia has been difficult, probably due in large part to genetic heterogeneity and multigenic inheritance of genes of small affect.Recently, two overlapping genes, G72 and G30, which are transcribed in the brain, spanning a 65 kb segment from chromosome 13q34 were shown to be significantly associated schizophrenia. Interestingly, G72 protein interacts with the gene for D-amino acid oxidase (DAAO) on 12q24 to regulate glutaminergic signaling through the N-methyl-D-aspartate (NMDA) receptor pathway. In addition, the Chromogranin B (CHGB) gene also has been proposed as a candidate gene for predisposition to schizophrenia due to its location on the genome, the evidence of genetic studies, and its functional role in schizophrenia.To further investigate the role of the G72/G30 and CHGB gene locus in schizophrenia susceptibility, we genotyped six single-nucleotide polymorphisms (SNPs: rs3916965, rs3916967, rs2391191, rs778294, rs779293, and rs3918342) in the region of the G72/G30 gene in 1176 Han Chinese subjects (588 cases and 588 controls) and 365 Scottish subjects (183 cases and 182 controls), and eight SNPs (rs2300427, rs236145, IVS4+808A>G, IVS5+84C>A, 433G>A, 533G>A, 1058C>G, and 1104A>G) in the region of CHGB gene in 192 Han Chinese trios. In addition, we performed a meta-analysis of all published previous studies to deal with the ambiguities raised by inconsistent results among molecular genetic studies between G72/G30 and schizophrenia.Significant association between an allele of marker rs778293 in G72/G30 genes and schizophrenia was found in our Chinese samples (P = 0.0013), and replicated in the Scottish samples (P = 0.022). Linkage disequilibrium (LD) analysis revealed that four SNPs between rs3916965 and rs778294 were in LD, called block I, and the two distal SNPs (rs778293 and rs3918342) constituted a block II in both the Chinese and Scottish samples. We selected one SNP from each block (rs778294 from block I and rs778293 from block II), and then analyzed the haplotypes. A significant difference was observed for the common haplotype GC in the Chinese sample (P = 0.0145), and replicated in the Scottish sample (P = 0.003). On meta-analysis, we found a statistically significant association between rs778293 and schizophrenia in Asian populations, but no difference was found between cases and controls in the European populations.On the other hand, the G allele of IVS4+808A>G in CHGB gene showed a trend of over-transmission from heterozygous parents to affected offspring (P = 0.06), although no significant over-transmission was found for individual markers. Furthermore, a significant transmission was observed for the common haplotype G-G-A-G-C (P = 0.0018).Overall our data give further support to the existing evidence that G72/G30 and CHGB genes are involved in conferring susceptibility to schizophrenia.Brachydactyly type A2 (BDA2) is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes.BDA2 was first described by Mohr and Wriedt in a large Danish/Norwegian kindred and mutations in the gene bone morphogenetic protein receptor 1B (BMPR1B) and growth/differentiation factor 5 (GDF5) were recently demonstrated in the affected families. As we know, the BMP/transforming growth factorβ(TGF-β) pathway plays a central role in skeletal development, and signaling of the TGF-βsuper-family members requires binding of ligands to cell surface receptors consisting of two kinds of transmembrane serine-threonine kinase receptors classified as types I and II. Two BMP type I receptors (BMPR1A and BMPR1B) and one type II receptor (BMPR2) are presently known.To identify the gene that cause BDA2 in Chinese affected family, we performed molecular analyses in four candidate genes (BMPR1B, GDF5, BMPR1A, and BMPR2). The molecular analyses included linkage analysis for micro-satellites markers flanking BMPR1B, GDF5, BMPR1A, and BMPR2, and sequencing of these genes. Actually, it is important to find one or more candidate gene of genetic diseases for the basic study and will provide definite clue for the pathology and physiology of disease.Unfortunately, we did not find any evidence for the linkage of the disease to these genes region. At the same time, the sequence analyses of the BDA2 causing gene, BMPR1B and GDF5, in the affected family members, did not identify any mutations, so did the candidate genes BMPR1A and BMPR2.Above all, our study suggested that a third BDA2 locus exists, and indicated the existence of genetic heterogeneity in the BDA2.In current study, we amplified the gene segments in the genome wide by use of micro-satellites or SNP markers. The technique we applied is high-throughput and precise and the great amount of sample with right diagnosis is another advantage, which can reduce analysis error and enhance its efficiency.