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

• Published in: Human molecular genetics 2006-04, Vol.15 (7), p.1151-1158
• 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, Toda, Tatsushi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; alpha-Synuclein - genetics; Biological and medical sciences; Case-Control Studies; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Humans; Linkage Disequilibrium; Male; Medical sciences; Middle Aged; Molecular and cellular biology; Neurology; Parkinson Disease - genetics; Polymorphism, Single Nucleotide
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddl030

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.