Abstract
Recently, Pimm et al. identified Epsin 4 on chromosome 5q33 as a susceptibility gene for schizophrenia in the British population, based on linkage and association evidence. In Pimm's case-control study, both the single polymorphisms and the individual haplotypes at the 5′ end of the gene showed genetic association with schizophrenia. Here, we report the first study evaluating the relevance of Epsin 4 and schizophrenia outside the British population. Markers showing positive results in the original work as well as two additional polymorphisms were genotyped in 308 Han Chinese family trios. Transmission disequilibrium analysis was used to test for association of single-locus markers and multi-locus haplotypes with schizophrenia. Although no individual marker was significant at the P=0.05 level, the haplotypes detected in our samples, different from those previously reported, showed strong evidence of association (most significant global P=0.0021). Our results indicate the presence of a locus near the 5′ end of Epsin 4 conferring susceptibility to the disease and provide further support for Epsin 4 as an important potential contributor to genetic risk in schizophrenia.
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References
Hyman SE . The NIMH perspective: next steps in schizophrenia research. Biol Psychiatry 2000; 47: 1–7.
Harrison PJ, Owen MJ . Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 2003; 361: 417–419.
Cloninger CR . The discovery of susceptibility genes for mental disorders. Proc Natl Acad Sci USA 2002; 99: 13365–13367.
Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.
Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci USA 2002; 99: 13675–13680.
Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.
Pimm J, McQuillin A, Thirumalai S, Lawrence J, Quested D, Bass N et al. The Epsin 4 gene on chromosome 5q, which encodes the clathrin-associated protein enthoprotin, is involved in the genetic susceptibility to schizophrenia. Am J Hum Genet 2005; 76: 902–907.
Gurling HM, Kalsi G, Brynjolfson J, Sigmundsson T, Sherrington R, Mankoo BS et al. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21–22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3–24 and 20q12.1–11.23. Am J Hum Genet 2001; 68: 661–673.
Paunio T, Ekelund J, Varilo T, Parker A, Hovatta I, Turunen JA et al. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum Mol Genet 2001; 10: 3037–3048.
Schwab SG, Eckstein GN, Hallmayer J, Lerer B, Albus M, Borrmann M et al. Evidence suggestive of a locus on chromosome 5q31 contributing to susceptibility for schizophrenia in German and Israeli families by multipoint affected sib-pair linkage analysis. Mol Psychiatry 1997; 2: 156–160.
Straub RE, MacLean CJ, O'Neill FA, Walsh D, Kendler KS . Support for a possible schizophrenia vulnerability locus in region 5q22–31 in Irish families. Mol Psychiatry 1997; 2: 148–155.
Devlin B, Bacanu SA, Roeder K, Reimherr F, Wender P, Galke B et al. Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau. Mol Psychiatry 2002; 7: 689–694.
Wasiak S, Legendre-Guillemin V, Puertollano R, Blondeau F, Girard M, de Heuvel E et al. Enthoprotin: a novel clathrin-associated protein identified through subcellular proteomics. J Cell Biol 2002; 158: 855–862.
Spitzer RL, Williams JB, Gibbon M, First MB . The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 1992; 49: 624–629.
Germer S, Holland MJ, Higuchi R . High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR. Genome Res 2000; 10: 258–266.
Chen Q, He G, Qin W, Chen QY, Zhao XZ, Duan SW et al. Family-based association study of synapsin II and schizophrenia. Am J Hum Genet 2004; 75: 873–877.
Dudbridge F . Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
Shi YY, He L . SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci. Cell Res 2005; 15: 97–98.
Schaid DJ . Transmission disequilibrium, family controls, and great expectations. Am J Hum Genet 1998; 63: 935–941.
Ding YC, Wooding S, Harpending HC, Chi HC, Li HP, Fu YX et al. Population structure and history in East Asia. Proc Natl Acad Sci USA 2000; 97: 14003–14006.
Shi Y, Zhao X, Yu L, Tao R, Tang J, La Y et al. Genetic structure adds power to detect schizophrenia susceptibility at SLIT3 in the Chinese Han population. Genome Res 2004; 14: 1345–1349.
Marchini J, Donnelly P, Cardon LR . Genome-wide strategies for detecting multiple loci that influence complex diseases. Nat Genet 2005; 37: 413–417.
Jorde LB . Linkage disequilibrium and the search for complex disease genes. Genome Res 2000; 10: 1435–1444.
Acknowledgements
This work was supported by the Key grant Project of Chinese Ministry of Education (No.10414), PRC, The national 863 projects (2001AA224011), The National tackle-key-problem project (2002BA711A07-01), The National Natural Science Foundation of China, The Shanghai Municipal Commission for Science and Technology. We were grateful to Professor Hugh Gurling for providing us with UK DNA samples and genotyping information.
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Tang, R., Zhao, X., Shi, Y. et al. Family-based association study of Epsin 4 and Schizophrenia. Mol Psychiatry 11, 395–399 (2006). https://doi.org/10.1038/sj.mp.4001780
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DOI: https://doi.org/10.1038/sj.mp.4001780
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