Familial genes in sporadic disease: Common variants of α-synuclein gene associate with Parkinson's disease

Ross, Owen A.; Gosal, David; Stone, Jeremy T.; Lincoln, Sarah; Heckman, Michael G.; Irvine, G. Brent; Johnston, Janet; Gibson, J. Mark; Farrer, Matthew J.; Lynch, Timothy

doi:10.1016/j.mad.2007.04.002

Cited by 56 publications

(49 citation statements)

References 19 publications

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“…This would suggest that REP1 and other promoter polymorphisms that modulate gene expression should also have an effect on age at onset, although the effect may not be as dramatic as gene multiplication and therefore more difficult to detect. One study has reported earlier disease onset in patients with the long REP1 allele (denoted 261 here) [Hadjigeorgiou et al, 2005], but others were unable to replicate [Maraganore et al, 2006;Ross et al, 2007;Winkler et al, 2007]. We did find evidence for association of REP1 with age at onset, although the effect was relatively small and marginally significant.…”

Section: Discussioncontrasting

confidence: 63%

“…Association of SNCA polymorphisms with common forms of PD, however, has been more difficult to establish, because their effect size on disease risk is much smaller than that of causative mutations, and also because of inherent confounders such as disease heterogeneity, which are more serious in association studies than in linkage studies. A large and growing body of evidence now points to polymorphisms in SNCA and its regulatory regions as being associated with susceptibility to common non-Mendelian forms of PD [Pals et al, 2004;Mellick et al, 2005;Mueller et al, 2005;Maraganore et al, 2006;Ross et al, 2007;Winkler et al, 2007]. The REP1 polymorphism, in particular, has a direct functional relevance to PD via its effect on gene expression [Chiba-Falek and Nussbaum, 2001;Chiba-Falek et al, 2003].…”

Section: Discussionmentioning

confidence: 99%

“…Several SNCA haplotype and polymorphisms have been implicated in PD, including single nucleotide polymorphisms (SNPs) in the 5 0 UTR/promoter region, and the 3 0 UTR [Pals et al, 2004;Mueller et al, 2005;Ross et al, 2007;Winkler et al, 2007]. A recent study reported on SNPs in the promoter that may be independently associated with PD [Winkler et al, 2007], which would imply their effects on PD risk may be cumulative to the REP1 effect.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, REP1 may be associated with susceptibility to PD via modulation of SNCA expression. Numerous studies have examined genetic association between REP1 allele length and susceptibility to PD [Farrer et al, 2001;Spadafora et al, 2003;Pals et al, 2004;Ross et al, 2007]. The individual studies were small and the results were inconsistent.…”

Section: Introductionmentioning

confidence: 99%

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Genetic association between α‐synuclein and idiopathic parkinson's disease

Kay

Factor

Samii

et al. 2008

American J of Med Genetics Pt B

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Point mutations and copy number variations in SNCA, the gene encoding alpha-synuclein, cause familial Parkinson's disease (PD). A dinucleotide polymorphism (REP1) in the SNCA promoter may be a risk factor for common forms of PD. We studied 1,802 PD patients and 2,129 controls from the NeuroGenetics Research Consortium, using uniform, standardized protocols for diagnosis, subject recruitment, data collection, genotyping, and data analysis. Three common REP1 alleles (257, 259, and 261 bp, with control frequencies of 0.28, 0.65, and 0.06) and several rare alleles (combined frequency <0.01) were detected. We confirmed association of REP1 with PD risk [odds ratio (OR) = 0.86, P = 0.006 for 257-carriers; OR = 1.25, P = 0.022 for 261-carriers]. Using a normalization procedure, we showed that the 257 and 261 alleles are both independently associated with PD risk (for 257, P = 0.002 in overall data, 0.003 in non-familial PD, 0.001 in early-onset PD; for 261, P = 0.056 in overall data, 0.024 in non-familial PD, 0.052 in early-onset PD). The 257-associated risk was consistent with a dominant model [hazard ratio (HR) = 0.99, P = 0.91 for 257/257 vs. 257/X where X denotes all other common alleles; HR = 1.16, P = 0.004 for X/X vs. 257/X]. The 261-associated risk was consistent with a recessive model (HR = 1.89, P = 0.026 for 261/261 vs. 261/X; HR = 0.95, P = 0.42 for X/X vs. 261/X). Genotype-specific mean onset ages (+/-SD) ranged from 54.8 +/- 12.1 for 261/261 to 59.4 +/- 11.5 for 257/257, displaying a trend of decreasing onset age with increasing allele size (P = 0.055). Genetic variation in SNCA and its regulatory regions play an important role in both familial and sporadic PD.

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Section: Discussioncontrasting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Genetic association between α‐synuclein and idiopathic parkinson's disease

Kay

Factor

Samii

et al. 2008

American J of Med Genetics Pt B

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“…Of the PD susceptibility variants that have been identified thus far, the best validated have involved those located in the α-synuclein ( SNCA ) gene, which also contains several pathogenic mutations that are linked to familial PD, and in the microtubule-associated protein tau ( MAPT ) gene (Gasser et al, 2011). More specifically, associations with PD have been identified in both Caucasian and Asian populations at the 3′ and 5′ ends of the SNCA gene (Mizuta et al, 2006; Mueller et al, 2005; Pankratz et al, 2009; Ross et al, 2007; Satake et al, 2009; Simón-Sánchez et al, 2009; Winkler et al, 2007), while the H1 haplotype in MAPT is associated with PD in Caucasians, but not in Asians owing to the almost complete absence of the H2 haplotype in that group (Evans et al, 2004; Healy et al, 2004; Skipper et al, 2004; Tobin et al, 2008; Wider et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Heckman

Elbaz

Soto‐Ortolaza

et al. 2014

Neurobiology of Aging

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The best validated susceptibility variants for Parkinson’s disease (PD) are located in the alpha-synuclein (SNCA) and microtubule-associated protein tau (MAPT) genes. Recently, a protective p.N551K-R1398H-K1423K haplotype in the leucine-rich repeat kinase 2 (LRRK2) gene was identified, with p.R1398H appearing to be the most likely functional variant. To date, the consistency of the protective effect of LRRK2 p.R1398H across MAPT and SNCA variant genotypes has not been assessed. To address this, we examined four SNCA variants (rs181489, rs356219, rs11931074, rs2583988), the MAPT H1-haplotype defining variant rs1052553, and LRRK2 p.R1398H (rs7133914) in Caucasian (N=10,322) and Asian (N=2,289) series. There was no evidence of an interaction of LRRK2 p.R1398H with MAPT or SNCA variants (all P≥0.10); the protective effect of p.R1398H was observed at similar magnitude across MAPT and SNCA genotypes, and the risk effects of MAPT and SNCA variants were observed consistently for LRRK2 p.R1398H genotypes. Our results indicate that the association of LRRK2 p.R1398H with PD is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.

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Alpha‐synuclein (SNCA) polymorphisms and susceptibility to Parkinson's disease: A meta‐analysis

Han

Liu²,

Mi³

et al. 2015

American J of Med Genetics Pt B

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It has been reported that single nucleotide polymorphisms (SNPs) of Alpha-synuclein (SNCA) are associated with Parkinson's disease (PD). Some researchers have attempted to validate this finding in various ethnic populations. The results of studies concerning SNCA polymorphisms and PD susceptibility remain conflicting. To evaluate the association between these SNPs and PD, the authors conducted a series of meta-analyses using a predefined protocol. Databases including PubMed, MEDLINE and PD gene were searched to identify relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. All analyses were calculated using STATA11.0. A total of 19 studies on the SNPS rs181489, rs356186, rs356219, rs894278, rs2583988, rs2619363, rs2619364, rs2737029, rs10005233 and rs11931074 were included. This meta-analysis showed that eight out of these 10 candidate SNPs may be associated with PD risk. Significant association was found between PD and the following SNPs: rs181489, rs356186, rs356219, rs894278 rs2583988, rs2619364, rs10005233 and rs11931074. Among these SNPs, rs356186 was found to be the only SNP that may play a protective role in Parkinson's disease. These results suggest that the SNCA gene may be associated with PD.

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Familial genes in sporadic disease: Common variants of α-synuclein gene associate with Parkinson's disease

Cited by 56 publications

References 19 publications

Genetic association between α‐synuclein and idiopathic parkinson's disease

Genetic association between α‐synuclein and idiopathic parkinson's disease

The protective effect of LRRK2 p.R1398H on risk of Parkinson's disease is independent of MAPT and SNCA variants

Alpha‐synuclein (SNCA) polymorphisms and susceptibility to Parkinson's disease: A meta‐analysis

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