Yasuo Tsukamoto

Mathematical basis of affected sib-pair analysis: an extension to X-linked loci

Most clinical genetic studies are done without knowing their mathematical basis. However, because the results of such studies rely on the correctness of the mathematical calculations involved, we cannot ignore the mathematics of genetic studies. In this study, the mathematical basis of the sib-pair method, which has been widely used in recent genome-wide studies, was extended to studies focusing on the X chromosome, and then applied to study a clinical microsatellite marker on the X chromosome. Our calculation involves classifying marker types on the X chromosome for an affected sib-pair and an unaffected sib, together with their sexual information and the possible parental marker types applicable to a genome-wide genetic study. The method proposed in this study was then applied to 41 Japanese rheumatoid families, and the locus DXS984 was found to be most likely to be linked with rheumatoid arthritis (RA). This locus, which we found nicely, was also highlighted in a previous study that used the Mapmaker/sibs program, so we can conclude that our calculation provides a solid foundation for understanding and confirming the results obtained using the sib-pair method.

Notes on the Disease Mechanism and Genetics of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic polyarthritis of unknown etiology that affects about 1% of the population worldwide. The risk of the disease in the siblings of affected individuals (λ s ) is significantly increased in RA, suggesting that both genetic and environment factors are important in the pathogenesis of RA. Previous studies in this laboratory have shown that features characteristic to RA, synovial overgrowth and bone resorption, can be experimentally reproduced by augmenting the expression of the c-fos protooncogene. We have searched the human genome for genes that predispose to RA using fluorescence-based microsatellite marker analysis and affected sib-pair linkage study. A panel of 41 Japanese families, each with at least two affected siblings, was typed for genome-wide 358 polymorphic microsatellite marker loci. Three principal chromosome regions of linkage, D1S253/214, D8S556 and DXS1232, have been identified which we call RAI, RA2 and RA3 for rheumatoid arthritis disease loci.