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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.

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The relationship between Raman spectra and crystallographic orientation was examined for single crystals of Fo 89 Fa 11 olivine [(Mg 0.89 Fe 0.11 ) 2 SiO 4 ]. Raman spectra were obtained for chemically homogeneous olivine grains with various orientations on a thin section of mantle-derived rock (dunite) using micro-Raman equipment and an unpolarized exciting laser. Crystallographic orientations of each olivine grain were determined using an electron backscattered diffraction (EBSD) method. Five apparent peaks at 822 (peak 1), 854 (peak 2), 880 (peak 3), 917 (peak 4), and 959 cm −1 (peak 5) were observed in the spectral range of 700-1050 cm −1 . Intensity ratios of peak i to peak 2, I i /I 2 , for i = 1, 4, and 5 were formulated empirically as functions of crystallographic orientations: I i /I 2 = .a 1i q 2 /p 2 + a 2i q/p + a 3i / sin 2 f + .b 1i q 2 /p 2 + b 2i q/p + b 3i / sin f + c i where a 1i , a 2i , a 3i , b 1i , b 2i , b 3i , c i are constants. f is the angle between the [100] axis and the incident direction of the laser, and q is the angle between the [001] axis and the incident direction of laser projected on the f100g plane. These equations well describe the relationships between I i /I 2 and crystallographic orientation. The obtained empirical equations enable Raman spectroscopic determination of the crystallographic orientation of olivine.