Multiple candidate gene analysis identifies [alpha]-synuclein as a susceptibility gene for sporadic Parkinson's disease

• Published in: Human molecular genetics Vol. 15; no. 7; p. 1151
• Main Authors: Mizuta, Ikuko, Satake, Wataru, Nakabayashi, Yuko, Ito, Chiyomi, Suzuki, Satoko, Momose, Yoshio, Nagai, Yoshitaka, Oka, Akira, Inoko, Hidetoshi, Fukae, Jiro, Saito, Yuko, Sawabe, Motoji, Murayama, Shigeo, Yamamoto, Mitsutoshi, Hattori, Nobutaka, Murata, Miho
• Format: Journal Article
• Language: English
• Published: Oxford Oxford Publishing Limited (England) 01.04.2006
• ISSN: 0964-6906; 1460-2083

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 α-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0×10-10). 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=2.0×10-9-1.7×10-11). 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.