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Human Molecular Genetics Advance Access originally published online on July 6, 2005
Human Molecular Genetics 2005 14(16):2305-2321; doi:10.1093/hmg/ddi234
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© The Author 2005. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oupjournals.org

Whole genome association study of rheumatoid arthritis using 27 039 microsatellites

Gen Tamiya1,2, Minori Shinya1,2, Tadashi Imanishi3, Tomoki Ikuta1,2, Satoshi Makino1, Koichi Okamoto1,2,4, Koh Furugaki1,2,4, Toshiko Matsumoto5, Shuhei Mano1, Satoshi Ando1, Yasuyuki Nozaki5, Wataru Yukawa2,5, Ryo Nakashige5, Daisuke Yamaguchi5, Hideo Ishibashi2,6, Manabu Yonekura2,7, Yuu Nakami2,5, Seiken Takayama7, Takaho Endo1, Takuya Saruwatari2,8, Masaru Yagura1, Yoko Yoshikawa9, Kei Fujimoto1, Akira Oka1, Suenori Chiku10, Samuel E.V. Linsen11, Marius J. Giphart11, Jerzy K. Kulski1,12, Toru Fukazawa13, Hiroshi Hashimoto13, Minoru Kimura1, Yuuichi Hoshina14, Yasuo Suzuki14, Tomomitsu Hotta14, Joji Mochida15, Takatoshi Minezaki15, Koichiro Komai16, Shunichi Shiozawa16, Atsuo Taniguchi17, Hisashi Yamanaka17, Naoyuki Kamatani2,17, Takashi Gojobori2,18, Seiamak Bahram19 and Hidetoshi Inoko1,2,3,*

1Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan, 2Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan, 3Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan, 4Chugai Pharmaceutical Corporation Ltd., Gotemba, Shizuoka 412-8513, Japan, 5Hitachi Software Engineering Corporation, Ltd., Tokyo 140-002, Japan, 6Applied Biosystems Japan Ltd., Tokyo 104-0032, Japan, 7Mitsui Knowledge Industry Corporation Ltd., Tokyo 164-8555, Japan, 8NTT DATA Corporation Ltd., Tokyo 135-6033, Japan, 9Nisshinbo Industries Inc., Chiba, Chiba 267-0056, Japan, 10Fuji Research Institute Corporation Ltd., Tokyo 101-0054, Japan, 11Department of ImmunoHaematology and Blood Transfusion, Leiden University Medical Center, 2300RC Leiden, The Netherlands, 12Centre for Bioinformatics and Biological Computing, School of Information Technology, Murdoch University, Murdoch, Weatern Australia 6150, Australia, 13Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo 113-8421, Japan, 14Department of Hematology, Rheumatology and Endocrinology, Course of Medical Science, and 15Department of Orthopedics Surgery, Course of Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan, 16Department of Rheumatology, Faculty of Health Science, School of Medicine, Kobe University, Kobe, Hyougo 654-0142, Japan, 17Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-8666, Japan, 18Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan and 19INSERM-CReS, Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, 67085 Strasbourg, France

* To whom correspondence should be addressed. Tel: +81 463-93-1121, ext. 2312; Fax: +81 463-94-8884; E.mail: hinoko{at}is.icc.u-tokai.ac.jp

Received April 29, 2005; Revised June 15, 2005; Accepted June 28, 2005

A major goal of current human genome-wide studies is to identify the genetic basis of complex disorders. However, the availability of an unbiased, reliable, cost efficient and comprehensive methodology to analyze the entire genome for complex disease association is still largely lacking or problematic. Therefore, we have developed a practical and efficient strategy for whole genome association studies of complex diseases by charting the human genome at 100 kb intervals using a collection of 27 039 microsatellites and the DNA pooling method in three successive genomic screens of independent case–control populations. The final step in our methodology consists of fine mapping of the candidate susceptible DNA regions by single nucleotide polymorphisms (SNPs) analysis. This approach was validated upon application to rheumatoid arthritis, a destructive joint disease affecting up to 1% of the population. A total of 47 candidate regions were identified. The top seven loci, withstanding the most stringent statistical tests, were dissected down to individual genes and/or SNPs on four chromosomes, including the previously known 6p21.3-encoded Major Histocompatibility Complex gene, HLA-DRB1. Hence, microsatellite-based genome-wide association analysis complemented by end stage SNP typing provides a new tool for genetic dissection of multifactorial pathologies including common diseases.


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