Replication of MAPT and SNCA, but not PARK16-18, as susceptibility genes for Parkinson's disease

Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA.
Movement Disorders (Impact Factor: 5.68). 04/2011; 26(5):819-23. DOI: 10.1002/mds.23642
Source: PubMed


Recent genome-wide association studies of Parkinson's disease have nominated 3 new susceptibility loci (PARK16-18) and confirmed 2 known risk genes (MAPT and SNCA) in populations of European ancestry. We sought to replicate these findings. We genotyped single-nucleotide polymorphisms in each of these genes/loci in 1445 Parkinson's disease patients and 1161 controls from northern Spain. Logistic regression was used to test for association between genotype and Parkinson's disease under an additive model, adjusting for sex, age, and site. We also performed analyses stratified by age at onset. Single-nucleotide polymorphisms in MAPT (rs1800547; P = 3.1 × 10(-4) ) and SNCA (rs356219; P = 5.5 × 10(-4) ) were significantly associated with Parkinson's disease. However, none of the markers in PARK16-18 associated with Parkinson's disease in the overall sample, or in any age stratum, with P values ranging from .09 to .88. Although our data further validate MAPT and SNCA as Parkinson's disease susceptibility genes, we failed to replicate PARK16, PARK17, and PARK18. Potential reasons for the discordance between our study and previous genome-wide association studies include effects of population structure, power, and population-specific environmental interactions. Our findings suggest that additional studies of PARK16-18 are necessary to establish the role of these loci in modifying risk for Parkinson's disease in European-derived populations. © 2011 Movement Disorder Society.

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    • "Of interest, one of the two independent studies in Asians showed increased risk of PD associated with Rep1 variant, while the association was not replicated in the other study, suggesting variability of microsatellite region may influence the association (Tan et al., 2003). The SNCA single nucleotide polymorphisms (SNPs), such as rs2583988, rs2619364 and rs2619363 (in the 5 region), rs7684318 (in Intron 4), rs356165 and rs356219 (in the 3 region), also conveyed an increased risk of PD in Asians and Europeans (Fig. 1) (Mata et al., 2011; Mizuta et al., 2006; Myhre et al., 2008; Rajput et al., 2009; Ross et al., 2007; Winkler et al., 2007; Wu-Chou et al., 2013; Yu et al., 2010). "
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    ABSTRACT: Parkinson disease (PD; MIM 168600) is the second most common progressive neurodegenerative disorder characterized by a variety of motor and non-motor features. To date, at least 20 loci and 15 disease-causing genes for parkinsonism have been identified. Among them, the α-synuclein (SNCA) gene was associated with PARK1/PARK4. Point mutations, duplications and triplications in the SNCA gene cause a rare dominant form of PD in familial and sporadic PD cases. The α-synuclein protein, a member of the synuclein family, is abundantly expressed in the brain. The protein is the major component of Lewy bodies and Lewy neurites in dopaminergic neurons in PD. Further understanding of its role in the pathogenesis of PD through various genetic techniques and animal models will likely provide new insights into our understanding, therapy and prevention of PD.
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    • "Hamza et al. [2010] first reported an association between PD risk and the rs3129882 variant in the HLA-DRA gene (chromosome location: 32517508, OR ¼ 1.31, meta-analysis P ¼ 2.9 Â 10 À8 ) [Hamza et al., 2010]. However, subsequent studies failed to replicate this finding [Mata et al., 2011; Chiang et al., 2012; Sharma et al., 2012], suggesting the need for further analyses, especially in other races, to confirm the role of the HLA-DRA rs3129882 variant in PD. Here, we conducted a large case–control study to investigate rs11248051 and rs1564282 variants in GAK and HLA-DRA rs3129882 variant in a Taiwanese PD population. "
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    • "PD is the result of a loss of dopamine in the substantia nigra. Several studies demonstrated genetic markers for PD, such as a-synuclein (SNCA), MAPT, leucine-rich repeat kinase 2 gene (LRRK2), DJ-1, PARK16–18, (Mata et al., 2011). Recent studies also showed that genetic variants of leucine-rich repeat and Ig domain containing 1 (LINGO-1) gene could be risk factor for ET (Zhou et al., 2012) and polymorphism of leucine-rich repeat and Ig domain containing 2 (LINGO-2) is associated with risk of PD (Su et al., 2012). "
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