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.

Download full-text


Available from: Jon Infante,
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Ageing research reviews 04/2014; 15(1). DOI:10.1016/j.arr.2014.04.002 · 4.94 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent genome-wide association studies of Parkinson's disease (PD) in Caucasian populations have identified two new susceptibility loci, GAK and HLA-DRA; however, only limited information exists regarding the involvement of these genes in PD risk in other ethnic groups. Here, we examined whether these genetic effects were consistent in a Taiwanese PD population. In a total 900 participants, including 448 PD patients and 452 control subjects, we genotyped the rs11248051 and rs1564282 variants of GAK, and the rs3129882 variant of HLA-DRA. Logistic regression analysis was used to test for associations between genotype and PD under an additive model, adjusting for age and gender. Subjects with CT/TT genotypes of GAK rs11248051 had a modestly increased association with PD compared to those with CC genotype (OR = 1.37; 95% CI = 1.09, 1.87; P = 0.03). Carriers and non-carriers exhibited indistinguishable phenotypes in regards to clinical presentation and onset age. We observed no association between PD risk and GAK rs1564282 or HLA-DRA rs3129882 variant. The different genetic effects between Taiwanese and Caucasian populations may come from differences in population structure and geographic region-specific genetic-environmental interactions. In conclusion, our results supported the association between the rs11248051 variant in GAK and PD risk in a Taiwanese population. Future functional studies of GAK in neuronal degeneration are warranted to unravel its role in the pathogenetic mechanism of PD. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 12/2013; 162(8). DOI:10.1002/ajmg.b.32188 · 3.42 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Essential tremor (ET) and Parkinson's disease (PD) are two of the most common movement disorders. Tremors are the primary symptoms of ET and of some PD patients, the two are often mistaken for each other. Especially since there are no available differentiate tests for the tremor of ET or PD, the early diagnoses mainly based on clinical assessments of medical symptoms, family and medication history, and examination by physicians. There is increasing evidence suggesting an association between ET and PD, such as a similar tremor frequency, overlapping resting tremors (a typical PD tremor), postural tremors (mainly in ET patients) in both ET and PD patients, and many ET patients develop PD later in life. Although it is difficult to make a differential diagnosis of ET and tremor-dominant PD based on clinical assessment, recent developments of objective measurements, such as brain imaging, neuropathology, and genetic analysis, has opened a helpful window for distinguishing ET from PD. In this mini review, we included literatures of ET and PD studies and discussed various advanced methods for differential diagnosis between ET and PD such as neuroimaging, genetic markers, tremor intensity and frequency, and drug-responses.
    Frontiers in Cellular Neuroscience 07/2013; 7:118. DOI:10.3389/fncel.2013.00118 · 4.29 Impact Factor
Show more