Phactr2 and Parkinson's disease.

Attempts at replicating the first genome-wide association study (GWAS) in Parkinson's disease (PD) have not successfully identified genetic risk factors. The present study reevaluates data from the first GWAS and focuses on the SNP (rs11155313, located in the Phactr2 gene) with the lowest P-value in the Tier 2 patient-control series. We employed four case-control series to examine the nominated SNP rs11155313 and identified association in US (OR: 1.39, P=0.032), Canadian (OR: 1.41, P=0.014) and Irish (OR: 1.44, P=0.034) patient-control series, but not in the Norwegian series (OR: 1.15, P=0.27). When combining all four series the observed trend was statistically significant (OR: 1.30, P<0.001). This study shows that reappraisal of publicly available results of GWAS may help nominate new risk factors for PD.

Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson's disease.

Genetic variation of the alpha-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson's disease (PD) remains elusive. The present study identifies an association of common SNCA polymorphisms with disease susceptibility in a series of Irish PD patients. There is evidence for association with alternate regions, of protection and risk which may act independently/synergistically, within the promoter region (Rep1; OR: 0.59, 95% CI: 0.37-0.84) and the 3'UTR of the gene (rs356165; OR: 1.67, 95% CI: 1.08-2.58). Given previous reports of association a collaborative effort is required which may exploit global linkage disequilibrium patterns for SNCA and standardise polymorphic markers used in each population. It is now crucial to identify the susceptibility allele and elucidate its functionality which may generate a therapeutic target for PD.

Phenotypic associations of tau and ApoE in Parkinson's disease.

Overlaps in clinical, pathological and molecular features of Parkinson's disease (PD), dementing and motor tauopathies have prompted association studies in search of common genetic risk factors that may predispose or modify this spectrum of disorders. To explore possible phenotypic implications, we studied common tau and ApoE gene polymorphisms, associated with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and PD, in a clinically and pathologically characterized cohort of PD patients and aged control subjects. Our results reveal a novel association between PD-related hallucinations and H1H1 genotype. We also report an association between PDD and the presence of the ApoE epsilon4 allele. Better determination of subsets of PD patients based upon the presence of specific phenotypic features may improve the accuracy of association studies.

Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia.

The goal of genetic association studies is to identify common (>5%) risk factors in complex disease traits. Herein we describe the first replicable 'functional' risk allele for Parkinson's disease. The leucine-rich repeat kinase 2 (Lrrk2) G2385R substitution is associated with familial parkinsonism, late-, and early-onset Parkinson's disease in ethnic Chinese Taiwanese. Crucially, we provide evidence of identity-by-descent and suggest that Lrrk2 G2385R carriers originate from one ancestor some 4800 years ago, at the start of Chinese civilization. Moreover, our findings demonstrate that common genetic coding variants contribute to Parkinson's disease in a population specific manner which may have important implications for future genome-wide association studies.

Lack of evidence for association of Parkin promoter polymorphism (PRKN-258) with increased risk of Parkinson's disease.

Parkin (PRKN) mutations are a common cause of early-onset parkinsonism, however the role of this gene in typical late-onset Parkinson's disease (PD) remains unresolved. A single nucleotide polymorphism in the promoter region (PRKN-258; rs9347683) has been observed to associate with PD, affect age-at-onset (AAO) of symptoms, and to functionally effect differential expression of the PRKN transcript. In the present study, PRKN-258 did not associate with PD, and no evidence for an AAO effect was observed in three age and gender-matched Caucasian patient-control series from Norway, Ireland and the US. These data do not support a role for this common variant in PD etiology.

ELAVL4, PARK10, and the Celts.

Genetic variability in ELAVL4 located in the PARK10 locus was recently associated with age-at-onset (AAO) in a series of Parkinson's disease (PD) patients originating from the United States. We examined five markers spanning ELAVL4 in Norwegian, United States, and Irish PD case-control samples. No association was found between the examined markers and AAO or PD in Norwegian or US samples. However, ELAVL4 markers (rs967582 and rs3902720) were significantly associated with susceptibility to PD in our Irish series. Our data suggest that the association between ELAVL4 and PD previously observed might be explained by a Celtic-founder effect.

Pathogenicity of the Lrrk2 R1514Q substitution in Parkinson's disease.

An increasing number of nonsynonymous LRRK2 variants are being reported as putative pathogenic mutations. We identified one large kindred harboring the Lrrk2 R1514Q substitution; however, the variant did not segregate fully with disease. Combined analyses of three case-control series demonstrate that the R1514Q substitution is not associated with increased risk of disease (OR: 1.3; 95% CI: 0.6-2.8; P = 0.45). These findings highlight the importance of using family-based studies and multiple population screenings when examining the association of these polymorphic LRRK2 gene variants with Parkinson's disease.

Leucine-rich repeat kinase 1: a paralog of LRRK2 and a candidate gene for Parkinson's disease.

Leucine-rich repeat kinase 1 gene (LRRK1) on chromosome 15q26.3 is a paralog of LRRK2 in which multiple substitutions were recently linked to Parkinson's disease. We have examined the exon-intron structure of the gene and the expressed mRNA sequence in brain. LRRK1 sequencing analysis in 95 probands from families with autosomal dominant Parkinson's disease identified 23 variants, 14 of which are novel, with four resulting in non-synonymous amino acid substitutions. These four substitutions are rare and do not clearly segregate with disease within our families or associate with sporadic Parkinson's disease in a US case-control series. Subsequent sequencing of exon 26 encoding the kinase activation segment in an additional 360 probands identified one further synonymous variant, suggesting that LRRK1 variants are not a frequent cause of Parkinson's disease. The relative absence of substitutions within LRRK1 highlights a greater conservation of sequence than observed for LRRK2. Comparison of evolutionary interspecies sequences of LRRK1 and LRRK2 suggests they diverged from a common founder gene.