Human Molecular Genetics Advance Access published online on February 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl030
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1 Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan
* To whom correspondence should be addressed. Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain. PD is a complex disorder, with multiple genetic and environmental factors influencing disease risk. To identify susceptible genes for sporadic PD, we performed case-control association studies of 268 single nucleotide polymorphisms (SNPs) in 121 candidate genes. In two independent case-control populations, we found that a SNP in
Received December 22, 2005
Revised February 15, 2006
Accepted February 15, 2006
Article
Multiple candidate gene analysis identifies
Ikuko Mizuta 1,
Wataru Satake 1,
Yuko Nakabayashi 2,
Chiyomi Ito 2,
Satoko Suzuki 2,
Yoshio Momose 1,
Yoshitaka Nagai 1,
Akira Oka 3,
Hidetoshi Inoko 3,
Jiro Fukae 4,
Yuko Saito 5,
Motoji Sawabe 6,
Shigeo Murayama 7,
Mitsutoshi Yamamoto 8,
Nobutaka Hattori 4,
Miho Murata 9,
and
Tatsushi Toda 2 *
-synuclein as a susceptibility gene for sporadic Parkinson's disease
2 Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
3 Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan
4 Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
5 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan; Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
6 Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan
7 Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan
8 Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan
9 Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan
Tatsushi Toda, E-mail: toda{at}clgene.med.osaka-u.ac.jp
Abstract 
-synuclein (SNCA), rs7684318, showed the strongest association with PD (P = 5.0x10-10). Linkage disequilibrium (LD) analysis using 29 SNPs in a region around rs7684318 revealed that the entire SNCA gene lies within a single LD block (D'>0.9) spanning about 120 kb. A tight LD group (r2 > 0.85) of six SNPs, including rs7684318, associated most strongly with PD (P = 2.0 x 10 - 9 - 1.7x10 - 11). Haplotype association analysis did not show lower P-values than any single SNP within this group. SNCA is a major component of Lewy bodies, the pathological hallmark of PD. Aggregation of SNCA is thought to play a crucial role in PD. SNCA expression levels tended to be positively correlated to the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.
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