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.
Bibliographical noteFunding Information:
We would like to thank M. Tomizawa, E. Tokubo, A. Takaki, H. Ando, S. Adachi, K. Yoshida, Y. Makino, K. Kobayashi, T. Shinomiya, S. Harada, M. Matsuzawa and S. Yamamoto for technical assistance, T. Ichihara (Nisshinbo Research and Development Center), N. Yasuda and T. Tamura (JBIRC), S. Hashimoto and H. Sano (JBiC), Y. Eguchi (MKI), M. Morikawa (GenoDive Pharm) for suggestions or help in this work and finally J.-L. Mandel, M. Koenig (both at IGBMC) and J. Sibilia (Strasbourg University Hospital) for critical reading of the manuscript. This work was performed under the management of Japan Biological Informatics Consortium (JBIC) and supported by grants from the New Energy and Industrial Technology Development Organization (NEDO). This research was also supported by ‘Special Coordination Funds for Promoting Science and Technology’ from the Japan Science and Technology Agency and ‘Research for the Future Program’ from the Japan Society for the Promotion Science. S.B. and H.I. wish to thank an INSERM-JSPS collaborative grant. Funding to pay the Open Access publication charges for this article was provided by the grant from NEDO.
ASJC Scopus subject areas
- Molecular Biology