Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population
Introduction
Irregularities consistent with abnormal brain development, including faulty neuronal migration, altered spatial neuronal arrangement, and absence of significant gliosis, have been reported in schizophrenia. Together with behavioral, neuromotor, and other functional abnormalities that occur in childhood and predict schizophrenia, such as low IQ, poor motor skills, and poor development of language and social skills, these morphological findings indicate a developmental origin for schizophrenia (Crow, 1995, Benes et al., 1986).
Recent advances in the understanding of genes that regulate brain development offer insights into the mechanisms of developmental brain changes. One important issue is the identification of signaling pathways that coordinate changes in gene expression with dynamic changes in cell adhesion and migration, events that are important for the complex cellular architecture of the human brain. Although several growth factors affect both gene expression and cell migration, recent focus has been on the wnt signaling pathway (Clevers, 2006). wnts are powerful regulators of cell proliferation and differentiation, and their signaling pathway involves proteins that directly participate in both gene transcription and cell adhesion (currently > 150 genes (Li et al., 2006). Because schizophrenia involves developmental brain changes and abnormal neuronal and synaptic organization, alterations in the transduction of wnt signaling pathway may represent such a mechanism (Clevers, 2006, Emamian et al., 2004). The genetic associations of several wnt pathway genes and schizophrenia have been reported (Proitsi et al., 2008). As coordinate changes in gene expression are important for normal brain development, the present study focused on negative modulators of the wnt signaling pathway, KREMEN1 and DKK1.
wnt/beta-catenin signaling is inhibited by the secreted protein Dickkopf1, a member of a multigene family, which induces head formation in amphibian embryos (Niehrs, 2006). Dickkopf1 inhibits wnt signaling by triggering LRP5/6 internalization through formation of a ternary complex with Kremen receptors (Mao et al., 2002). DKK1 encodes a protein that is a member of the dickkopf family. This gene maps on chromosome 10 region q11.2, a region with suggestive linkage evidence for schizophrenia (Faraone et al., 1998). KREMEN1 encodes a high-affinity dickkopf homolog 1, a transmembrane receptor that functionally cooperates with dickkopf1 to block wnt/beta-catenin signaling. KREMEN1 maps to chromosome 22q12.1, relatively close to the region with weak, but suggestive linkage evidence for schizophrenia (Pulver et al., 1994).
We genotyped 16 common genetic variants within the aforementioned genes and examined their associations with schizophrenia. Additionally, we examined interactions between single nucleotide polymorphisms (SNPs) within KREMEN1 and DKK1.
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Materials and methods
Subjects comprised 1624 patients with schizophrenia (mean age, 46.5 ± 14.5 years) and 1621 volunteers with no personal or family history of psychiatric illness (mean age, 45.1 ± 14.0 years). Subjects were divided into a screening sample (n = 1681) and a confirmation sample (n = 1564). A general characterization and psychiatric assessment of subjects is available elsewhere (Ikeda et al., 2008). The screening and confirmation sample were collected independently at each university hospital. All subjects
Results
The results of the power analysis are presented in Table 1. We genotyped 16 tSNPs using the screening sample All tSNPs were in HWE, and the SNP-wise call rate was > 95%. The association signal was detected in allele-wise analysis at rs713526 as well as in the haplotype-wise analysis (Table 2). To deal with multiple testing issues and to keep the statistical power uncompromised, we performed additional genotyping of rs713526 using the confirmation sample. Although the direction of the association
Discussion
We conducted this study on two genes related to the wnt signaling pathway. The study is relatively large (> 3000 case-control subjects), and a pathway-based approach was used for candidate gene selection. Results of this study provide genetic evidence for the involvement of KREMEN1 locus in schizophrenia. The associated SNP is located in the promoter region of KREMEN1. This association was also observed in haplotype-wise analysis. The observed association at KREMEN1 locus was stronger in the
Role of funding source
Funding for this study was provided by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labor and Welfare of Japan; Grant-in-Aid for Scientific Research on Pathomechanisms of Brain Disorders from the Ministry of Education, Culture, Sports, Science and Technology of Japan; The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes; and the Core Research for Evolutional Science and
Contributors
BA, IK, YI and YN performed laboratory assays and the data-analysis. BA drafted the manuscript. HU, MS, TI, RH, MT, NI and NO participated in the design of the study, and coordinated sample collection. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors have no financial conflicts to declare.
Acknowledgements
We would like to express our gratitude to Dr Ryoko Ishihara for her technical assistance.
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