Abstract
There is strong evidence for a negative association between schizophrenia and rheumatoid arthritis (RA). However, the mechanism for this association is unknown. We hypothesize that these two diseases share susceptibility genes. Recently, extensive studies have identified some RA susceptibility genes, including NFKBIL1, SLC22A4, RUNX1, FCRL3 and PADI4, in the Japanese population. To assess whether polymorphisms in these RA susceptibility genes are implicated in vulnerability to schizophrenia, we conducted a two-stage case–control association study in Japanese subjects. In a screening population of 534 patients and 559 control subjects, we examined eight polymorphisms in RA susceptibility genes and found a potential association of padi4_94 in PADI4 with schizophrenia. However, we could not replicate this association in a confirmatory population of 2126 patients and 2228 control subjects. The results of this study suggest that these polymorphisms in RA susceptibility genes do not contribute to genetic susceptibility to schizophrenia.
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References
Mors, O., Mortensen, P. B. & Ewald, H. A population-based register study of the association between schizophrenia and rheumatoid arthritis. Schizophr. Res. 40, 67–74 (1999).
Oken, R. J. & Schulzer, M. At issue: schizophrenia and rheumatoid arthritis: the negative association revisited. Schizophr. Bull 25, 625–638 (1999).
Leucht, S., Burkard, T., Henderson, J., Maj, M. & Sartorius, N. Physical illness and schizophrenia: a review of the literature. Acta. Psychiatr. Scand. 116, 317–333 (2007).
Torrey, E. F. & Yolken, R. H. The schizophrenia-rheumatoid arthritis connection: infectious, immune, or both? Brain Behav. Immun. 15, 401–410 (2001).
Arinami, T., Otsuka, Y., Hamaguchi, H., Itokawa, M., Aoki, J., Shibuya, H. et al. Evidence supporting an association between the DRB1 gene and schizophrenia in Japanese. Schizophr. Res. 32, 81–86 (1998).
Sasaki, T., Matsushita, M., Nanko, S., Fukuda, R., Kennedy, J. L. & Tokunaga, K. Schizophrenia and the HLA-DRB1 gene in the Japanese population. Am. J. Psychiatry 156, 771–773 (1999).
Akaho, R., Matsushita, I., Narita, K., Okazaki, Y., Okabe, Y., Matsushita, M. et al. Support for an association between HLA-DR1 and schizophrenia in the Japanese population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96, 725–727 (2000).
Wakitani, S., Murata, N., Toda, Y., Ogawa, R., Kaneshige, T., Nishimura, Y. et al. The relationship between HLA-DRB1 alleles and disease subsets of rheumatoid arthritis in Japanese. Br. J. Rheumatol. 36, 630–636 (1997).
Kochi, Y., Yamada, R., Kobayashi, K., Takahashi, A., Suzuki, A., Sekine, A. et al. Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences. Arthritis. Rheum. 50, 63–71 (2004).
Okamoto, K., Makino, S., Yoshikawa, Y., Takaki, A., Nagatsuka, Y., Ota, M. et al. Identification of IkBL as the second major histocompatibility complex-linked susceptibility locus for rheumatoid arthritis. Am. J. Hum. Genet. 72, 303–312 (2003).
Tokuhiro, S., Yamada, R., Chang, X., Suzuki, A., Kochi, Y., Sawada, T. et al. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat. Genet. 35, 341–348 (2003).
Kochi, Y., Yamada, R., Suzuki, A., Harley, J. B., Shirasawa, S., Sawada, T. et al. A functional variant in FcRH3, encoding Fc receptor homolog 3, is associated with rheumatoid arthritis and several autoimmunities. Nat. Genet. 37, 478–485 (2005).
Suzuki, A., Yamada, R., Chang, X., Tokuhiro, S., Sawada, T., Suzuki, M. et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat. Genet. 34, 395–402 (2003).
Takata, Y., Inoue, H., Sato, A., Tsugawa, K., Miyatake, K., Hamada, D. et al. Replication of reported genetic associations of PADI4, FCRL3, SLC22A4 and RUNX1 genes with rheumatoid arthritis: results of an independent Japanese population and evidence from meta-analysis of East Asian studies. J. Hum. Genet. 53, 163–173 (2008).
Ikari, K., Kuwahara, M., Nakamura, T., Momohara, S., Hara, M., Yamada, H. et al. Association between PADI4 and rheumatoid arthritis: a replication study. Arthritis. Rheum. 52, 3054–3057 (2005).
Watanabe, Y., Muratake, T., Kaneko, N., Nunokawa, A. & Someya, T. No association between the brain-derived neurotrophic factor gene and schizophrenia in a Japanese population. Schizophr. Res. 84, 29–35 (2006).
Barrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).
Purcell, S., Cherny, S. S. & Sham, P. C. Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).
Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, L. E., Straub, R. E., Hovatta, I. et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: schizophrenia. Am. J. Hum. Genet. 73, 34–48 (2003).
Shirts, B. H., Kim, J. J., Reich, S., Dickerson, F. B., Yolken, R. H., Devlin, B. et al. Polymorphisms in MICB are associated with human herpes virus seropositivity and schizophrenia risk. Schizophr. Res. 94, 342–353 (2007).
Morar, B., Schwab, S. G., Albus, M., Maier, W., Lerer, B. & Wildenauer, D. B. Evaluation of association of SNPs in the TNF alpha gene region with schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 318–324 (2007).
de Bakker, P. I., Yelensky, R., Pe’er, I., Gabriel, S. B., Daly, M. J. & Altshuler, D. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217–1223 (2005).
Begovich, A. B., Carlton, V. E., Honigberg, L. A., Schrodi, S. J., Chokkalingam, A. P., Alexander, H. C. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).
Mori, M., Yamada, R., Kobayashi, K., Kawaida, R. & Yamamoto, K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J. Hum. Genet. 50, 264–266 (2005).
Acknowledgements
We thank the patients, their families and the healthy volunteers for their participation. This work was supported by a grant for the Promotion of Niigata University Research Projects (to YW).
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Watanabe, Y., Nunokawa, A., Kaneko, N. et al. Two-stage case–control association study of polymorphisms in rheumatoid arthritis susceptibility genes with schizophrenia. J Hum Genet 54, 62–65 (2009). https://doi.org/10.1038/jhg.2008.4
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DOI: https://doi.org/10.1038/jhg.2008.4
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