Multiple candidate gene analysis identifies α-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.

Genome-wide association study confirms extant PD risk loci among the Dutch

“…[6][7][8][25][26][27][28][29][30][31][32] The data presented here supports the hypothesis that two different signals in these blocks are present in the Dutch population, which is in controversy with previous results. 7,28,[30][31][32] In a report by Mueller et al, 25 the authors also detected two association signals in the 3¢ and 5¢ blocks of SNCA.…”

“…[6][7][8][25][26][27][28][29][30][31][32] In an effort to delineate the signal at this locus, we examined the LD structure across this region. This analysis revealed two LD blocks delimited at the intron 4 of SNCA as previously described [6][7][8]25 (Supplementary Figure 4).…”

Variants in the 3′UTR of SNCA do not affect miRNA-433 binding and alpha-synuclein expression

“…3 In idiopathic PD, several genetic association studies have suggested that the SCNA gene harbors significant risk haplotypes. 4 Recent genome-wide association studies in PD pointed to the 3 0 end of SNCA, which had already been implicated in the regulation of SNCA expression. [5][6][7] The 3 0 untranslated region (UTR) of SNCA carries various putative microRNA (miRNA) -binding sites that could have a role in SNCA expression and thus contribute to the susceptibility to develop PD.…”

Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

“…However, lack of evidences on the cosegregation suggested that other genetic factors should also be involved in the disease pathogenesis in the pedigrees with p.G2385R mutation. Analyses of p.G2385R in combination with recently identified genetic risk factors for PD such as SNCA [42][43][44] and GBA 45,46 would be important for evaluating the combined effects of these factors as well as for elucidating the molecular pathophysiology of PD.…”