title: Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease.
abstract: 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 alpha-synuclein (SNCA), rs7684318, showed the strongest association with PD (P=5.0 x 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 approximately 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)-1.7 x 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.
authors.affiliation: Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Mizuta
authors.forename: Wataru
authors.initials: W
authors.lastname: Satake
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakabayashi
authors.forename: Chiyomi
authors.initials: C
authors.lastname: Ito
authors.forename: Satoko
authors.initials: S
authors.lastname: Suzuki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Momose
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Akira
authors.initials: A
authors.lastname: Oka
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Inoko
authors.forename: Jiro
authors.initials: J
authors.lastname: Fukae
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.forename: Motoji
authors.initials: M
authors.lastname: Sawabe
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Toda
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein