ABSTRACT
The genetic basis of complex diseases is expected to be highly heterogeneous, with many disease genes, where each gene by itself has only a small effect. Based on the nonlinear contributions of disease genes across the genome to complex diseases, we introduce the concept of single nucleotide polymorphism (SNP) synergistic blocks. A two-stage approach is applied to detect the genetic association of synergistic blocks with a disease. In the first stage, synergistic blocks associated with a complex disease are identified by clustering SNP patterns and choosing blocks within a cluster that minimize a diversity criterion. In the second stage, a logistic regression model is given for a synergistic block. Using simulated case-control data, we demonstrate that our method has reasonable power to identify gene-gene interactions. To further evaluate the performance of our method, we apply our method to 17 loci of four candidate genes for paranoid schizophrenia in a Chinese population. Five synergistic blocks are found to be associated with schizophrenia, three of which are negatively associated (odds ratio, OR < 0.3, P < 0.05), while the others are positively associated (OR > 2.0, P < 0.05). The mathematical models of these five synergistic blocks are presented. The results suggest that there may be interactive effects for schizophrenia among variants of the genes neuregulin 1 (NRG1, 8p22-p11), G72 (13q34), the regulator of G-protein signaling-4 (RGS4, 1q21-q22) and frizzled 3 (FZD3, 8p21). Using synergistic blocks, we can reduce the dimensionality in a multi-locus association analysis, and evaluate the sizes of interactive effects among multiple disease genes on complex phenotypes.
Subject(s)
Genetic Predisposition to Disease/genetics , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , Algorithms , Case-Control Studies , Chromosome Mapping/methods , Chromosome Mapping/statistics & numerical data , Computer Simulation , Haplotypes , Humans , Linkage Disequilibrium , Models, Genetic , Neuronal Plasticity/genetics , Schizophrenia/geneticsABSTRACT
Frizzled 3 (FZD3) gene is located on chromosome 8p21, a region that has been implicated in schizophrenia in genetic linkage studies. The FZD3 is a transmembrane receptor required for Wnt signal transduction cascades that have been thought to be involved in producing the cytoarchitectural defects observed in schizophrenia. Previous work has showed a strong association between FZD3 locus and schizophrenia in family-based study. To confirm this issue further, we investigated a genetic association between four single nucleotide polymorphisms (SNPs) located in the FZD3 gene and schizophrenia by case-control study using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) in the Chinese Han population. Our studies showed the SNPs rs2323019 and rs880481 have significant differences in both genotype and allele frequencies between control subjects and schizophrenic patients (rs2323019: Allele A > G, chi2 = 6.7277, df = 1, P = 0.0095; Genotype, chi2 = 10.6583, df = 2, P = 0.0049; rs880481: Allele A > G, chi2 = 10.3945, df = 1, P = 0.0013; Genotype, chi2 = 16.8049, df = 2, P = 0.0002). In addition, we constructed three-locus haplotypes to test their association with schizophrenia. The globe chi-squared test for haplotype analysis showed a significant association (chi2 = 66.38, df = 7, P < 0.000001). These results suggested that the FZD3 gene might be involved in the predisposition to schizophrenia.
Subject(s)
Haplotypes , Receptors, G-Protein-Coupled/genetics , Schizophrenia/genetics , Adult , Alleles , Chi-Square Distribution , China , DNA/genetics , DNA/isolation & purification , Female , Frizzled Receptors , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Polymorphism, Restriction Fragment Length , Polymorphism, Single NucleotideABSTRACT
Several genomewide screens indicated that chromosome 7q was linked to autistic disorder. FOXP2, located on 7q31, is a putative transcription factor containing a polyglutamine tract and a forkhead DNA binding domain. It is one member of the forkhead family who are known to be key regulators of embryogenesis. A point mutation at a highly conserved residue within the forkhead domain co-segregated with affected status in the KE family who was a unique three generation pedigree with a severe speech and language disorder and FOXP2 was directly disrupted by a translocation in an individual who had similar deficits as those of the KE family. Several studies have investigated the role of FOXP2 polymorphisms in autism and none of them found positive association. We performed a family-based association study of three single nucleotide polymorphisms (SNPs) of FOXP2 in 181 Chinese Han trios using the analyses of transmission/disequilibrium test (TDT) and haplotype. We found a significant association between autistic disorder and one SNP, as well as with specific haplotypes formed by this SNP with two other SNPs we investigated. Our findings suggest that the FOXP2 gene may be involved in the pathogenesis of autism in Chinese population.
Subject(s)
Autistic Disorder/genetics , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Alleles , Autistic Disorder/pathology , China , DNA/genetics , DNA/metabolism , Deoxyribonucleases, Type II Site-Specific/metabolism , Female , Forkhead Transcription Factors , Gene Frequency , Genotype , Humans , Linkage Disequilibrium , Male , Nuclear Family , Polymorphism, Restriction Fragment LengthABSTRACT
The FZD3 protein is a transmembrane receptor for secreted Wnt glycoproteins involved in the Wnt signal transduction cascades. The alteration of Wnt signal transduction cascades has been thought to be involved in producing the cytoarchitectural defects observed in schizophrenia. Because the human FZD3 gene is mapped to chromosome 8p21, which is a potential region containing a gene for schizophrenia, it may play a role in conferring susceptibility to the disease. This study was conducted with the detection of three single nucleotide polymorphisms (SNPs) located within the FZD3 locus by using the polymerase chain reaction-based restriction fragment length polymorphism (RFLP) analysis among 246 schizophrenic family trios of Chinese Han descent.The transmission disequilibrium test (TDT) demonstrated that the three SNPs all showed a preferential transmission with a p value ranging from.0003-.000007. The global chi-squared test for haplotype transmission also showed a strong association (chi(2) = 48.84, df = 7, p <.000001).The strong association between the FZD3 locus and schizophrenia suggests that the gene itself may play a role in underlying schizophrenia, although a nearby gene responsible for predisposing to the illness cannot be ruled out.
Subject(s)
Receptors, G-Protein-Coupled/genetics , Schizophrenia/genetics , Chromosomes, Human, Pair 8 , Female , Frizzled Receptors , Genetic Predisposition to Disease , Genotype , Humans , Male , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single NucleotideABSTRACT
An increasing amount of evidence suggests that the pathophysiology of schizophrenia is associated with the abnormal immune system, and cytokines may be important in schizophrenia. Among these cytokines, interleukin-1beta may play a role in the pathogenesis of the disease. In the present study, we investigated the genetic association between a TaqI polymorphism in interleukin-1beta gene (IL-1beta) and schizophrenia by restriction fragment length polymorphism (RFLP) analysis among 132 Chinese families of Han descent. The transmission disequilibrium test (TDT) did not demonstrate an allelic association with schizophrenia. Our results suggested that the TaqI polymorphism in IL-1beta gene might not confer increased susceptibility for schizophrenia.