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.
Department of Molecular Life Science, Course of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, Bohseidai, Kanagawa, Japan.
Gen
G
Tamiya
Minori
M
Shinya
Tadashi
T
Imanishi
Tomoki
T
Ikuta
Satoshi
S
Makino
Koichi
K
Okamoto
Koh
K
Furugaki
Toshiko
T
Matsumoto
Shuhei
S
Mano
Satoshi
S
Ando
Yasuyuki
Y
Nozaki
Wataru
W
Yukawa
Ryo
R
Nakashige
Daisuke
D
Yamaguchi
Hideo
H
Ishibashi
Manabu
M
Yonekura
Yuu
Y
Nakami
Seiken
S
Takayama
Takaho
T
Endo
Takuya
T
Saruwatari
Masaru
M
Yagura
Yoko
Y
Yoshikawa
Kei
K
Fujimoto
Akira
A
Oka
Suenori
S
Chiku
Samuel E V
SE
Linsen
Marius J
MJ
Giphart
Jerzy K
JK
Kulski
Toru
T
Fukazawa
Hiroshi
H
Hashimoto
Minoru
M
Kimura
Yuuichi
Y
Hoshina
Yasuo
Y
Suzuki
Tomomitsu
T
Hotta
Joji
J
Mochida
Takatoshi
T
Minezaki
Koichiro
K
Komai
Shunichi
S
Shiozawa
Atsuo
A
Taniguchi
Hisashi
H
Yamanaka
Naoyuki
N
Kamatani
Takashi
T
Gojobori
Seiamak
S
Bahram
Hidetoshi
H
Inoko
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