Human Molecular Genetics Advance Access originally published online on February 24, 2006
Human Molecular Genetics 2006 15(7):1151-1158; doi:10.1093/hmg/ddl030
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Multiple candidate gene analysis identifies 
-synuclein as a susceptibility gene for sporadic Parkinson's disease
1Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan, 2Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan, 3Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 259-1193, Japan, 4Department of Neurology, Juntendo University School of Medicine, Tokyo 113-8421, Japan, 5Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo 173-0015, Japan, 6Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan, 7Department of Neurology, Kagawa Prefectural Central Hospital, Takamatsu 760-8557, Japan and 8Department of Neurology, Musashi Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan
* To whom correspondence should be addressed. Tel: +81 668793380; Fax: +81 668793389; Email: toda{at}clgene.med.osaka-u.ac.jp
Received December 22, 2005; Accepted February 15, 2006
Parkinson's disease (PD), one of the most common human neurodegenerative diseases, is characterized by the 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 
-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 
120 kb. A tight LD group (r2>0.85) of six SNPs, including rs7684318, associated most strongly with PD (P=2.0x10–9–1.7x10–11). 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 with the number of the associated allele in autopsied frontal cortices. These findings establish SNCA as a definite susceptibility gene for sporadic PD.
Present address: Department of Clinical Bioinformatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
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