Journal Article

Whole genome association study of rheumatoid arthritis using 27 039 microsatellites

Gen Tamiya, Minori Shinya, Tadashi Imanishi, Tomoki Ikuta, Satoshi Makino, Koichi Okamoto, Koh Furugaki, Toshiko Matsumoto, Shuhei Mano, Satoshi Ando, Yasuyuki Nozaki, Wataru Yukawa, Ryo Nakashige, Daisuke Yamaguchi, Hideo Ishibashi, Manabu Yonekura, Yuu Nakami, Seiken Takayama, Takaho Endo, Takuya Saruwatari, Masaru Yagura, Yoko Yoshikawa, Kei Fujimoto, Akira Oka, Suenori Chiku, Samuel E.V. Linsen, Marius J. Giphart, Jerzy K. Kulski, Toru Fukazawa, Hiroshi Hashimoto, Minoru Kimura, Yuuichi Hoshina, Yasuo Suzuki, Tomomitsu Hotta, Joji Mochida, Takatoshi Minezaki, Koichiro Komai, Shunichi Shiozawa, Atsuo Taniguchi, Hisashi Yamanaka, Naoyuki Kamatani, Takashi Gojobori, Seiamak Bahram and Hidetoshi Inoko

in Human Molecular Genetics

Volume 14, issue 16, pages 2305-2321
Published in print August 2005 | ISSN: 0964-6906
Published online July 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi234

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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.

Journal Article.  12456 words.  Illustrated.

Subjects: Genetics and Genomics

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