Whole genome association study of rheumatoid arthritis using 27 039 microsatellites.
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.
Tamiya
Gen
G
Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Kanagawa, Japan.
Shinya
Minori
M
Imanishi
Tadashi
T
Ikuta
Tomoki
T
Makino
Satoshi
S
Okamoto
Koichi
K
Furugaki
Koh
K
Matsumoto
Toshiko
T
Mano
Shuhei
S
Ando
Satoshi
S
Nozaki
Yasuyuki
Y
Yukawa
Wataru
W
Nakashige
Ryo
R
Yamaguchi
Daisuke
D
Ishibashi
Hideo
H
Yonekura
Manabu
M
Nakami
Yuu
Y
Takayama
Seiken
S
Endo
Takaho
T
Saruwatari
Takuya
T
Yagura
Masaru
M
Yoshikawa
Yoko
Y
Fujimoto
Kei
K
Oka
Akira
A
Chiku
Suenori
S
Linsen
Samuel E V
SE
Giphart
Marius J
MJ
Kulski
Jerzy K
JK
Fukazawa
Toru
T
Hashimoto
Hiroshi
H
Kimura
Minoru
M
Hoshina
Yuuichi
Y
Suzuki
Yasuo
Y
Hotta
Tomomitsu
T
Mochida
Joji
J
Minezaki
Takatoshi
T
Komai
Koichiro
K
Shiozawa
Shunichi
S
Taniguchi
Atsuo
A
Yamanaka
Hisashi
H
Kamatani
Naoyuki
N
Gojobori
Takashi
T
Bahram
Seiamak
S
Inoko
Hidetoshi
H
D001172:Arthritis, Rheumatoid / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D004247:DNA