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Human Molecular Genetics Advance Access published online on July 6, 2005
Human Molecular Genetics, 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
Received April 29, 2005
Revised June 15, 2005
Accepted June 28, 2005

Article

Whole genome association study of rheumatoid arthritis using 27,039 microsatellites

Gen Tamiya 1, Minori Shinya 1, Tadashi Imanishi 2, Tomoki Ikuta 1, Satoshi Makino 3, Koichi Okamoto 4, Koh Furugaki 4, Toshiko Matsumoto 5, Shuhei Mano 3, Satoshi Ando 3, Yasuyuki Nozaki 5, Wataru Yukawa 6, Ryo Nakashige 5, Daisuke Yamaguchi 5, Hideo Ishibashi 7, Manabu Yonekura 7, Yuu Nakami 6, Seiken Takayama 8, Takaho Endo 3, Takuya Saruwatari 9, Masaru Yagura 3, Yoko Yoshikawa 10, Kei Fujimoto 3, Akira Oka 3, Suenori Chiku 11, Sammuel E.V. Linsen 12, Marius J. Giphart 12, Jerzy K. Kulski 13, Toru Fukazawa 14, Hiroshi Hashimoto 14, Minoru Kimura 3, Yuuichi Hoshina 15, Yasuo Suzuki 15, Tomomitsu Hotta 15, Joji Mochida 16, Takatoshi Minezaki 16, Koichiro Komai 17, Shunichi Shiozawa 17, Atsuo Taniguchi 18, Hisashi Yamanaka 18, Naoyuki Kamatani 19, Takashi Gojobori 20, Seiamak Bahram 21, and Hidetoshi Inoko 22*

1 Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan; Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan
2 Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
3 Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan
4 Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan; Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Chugai Pharmaceutical Corporation Ltd., Gotemba, Shizuoka 412-8513, Japan
5 Hitachi Software Engineering Corporation, Ltd., Yokohama, Kanagawa 230-0045, Japan
6 Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Hitachi Software Engineering Corporation, Ltd., Yokohama, Kanagawa 230-0045, Japan
7 Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Applied Biosystems Japan Ltd., Tokyo 104-0032, Japan
8 Mitsui Knowledge Industry Corporation Ltd., Tokyo 164-8555, Japan
9 Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; NTT DATA Corporation Ltd., Tokyo 135-6033, Japan
10 Nisshinbo Industries Inc., Chiba, Chiba 267-0056, Japan
11 Fuji Research Institute Corporation Ltd., Tokyo 101-0054, Japan
12 Department of ImmunoHaematology and Blood Transfusion, Leiden University Medical Center, 2300RC Leiden, The Netherlands
13 Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan; Centre for Bioinformatics and Biological Computing, School of Information Technology, Murdoch University, Murdoch, Weatern Australia 6150, Australia
14 Department of Rheumatology and Internal Medicine, Juntendo University, Tokyo 113-8421, Japan
15 Department of Hematology Rheumatology and Endocrinology, Course of Medical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
16 Department of Orthopedics Surgery, Course of Surgical Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
17 Department of Rheumatology, Faculty of Health Science, School of Medicine, Kobe University, Kobe, Hyougo 654-0142, Japan
18 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
19 Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-8666, Japan
20 Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Nisshinbo Industries Inc., Chiba, Chiba 267-0056, Japan; Center for Information Biology and DNA Data Bank of Japan, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan
21 INSERM-CReS, Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, 67085 Strasbourg, France
22 Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan; Japan Biological Information Research Center, Japan Biological Informatics Consortium, Tokyo 135-0064, Japan; Biological Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan

* To whom correspondence should be addressed.
Hidetoshi Inoko, E-mail: hinoko{at}is.icc.u-tokai.ac.jp


  Abstract

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. We have therefore 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 (SNP) analysis. This approach was validated upon application to rheumatoid arthritis (RA), 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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