Background-Recent studies indicate an increased frequency of mutations in the gene for Gaucher disease, glucocerebrosidase (GBA), among patients with Parkinson disease. An international collaborative study was conducted to ascertain the frequency of GBA mutations in ethnically diverse patients with Parkinson disease.

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The recent hapmap effort has placed focus on the application of genome-wide SNP analysis to assess the contribution of genetic variability, particularly SNPs, to traits such as disease. Here, we describe the utility of genome-wide SNP analysis in the direct detection of extended homozygosity and structural genomic variation. We use this approach to assess the frequency of genomic alterations resulting from the lymphoblast immortalization and culture processes commonly used in cell repositories. We have assayed 408 804 SNPs in 276 DNA samples extracted from Epstein-Barr virus immortalized cell lines, which were derived from lymphocytes of elderly neurologically normal subjects. These data reveal extended homozygosity (contiguous tracts>5 Mb) in 9.5% (26/272) and 340 structural genomic alterations in 182 (66.9%) DNA samples assessed, 66% of which did not overlap with previously described structural variations. Examination of DNA extracted directly from the blood of 30 of these subjects confirmed all examined instances of extended homozygosity (6/6), 75% of structural genomic alteration <5 Mb in size (12/16) and 13% (1/8) of structural genomic alteration >5 Mb in size. These data suggest that structural genomic variation is a common phenomenon in the general population. While a proportion of this variability may be caused or its relative abundance altered by the immortalization and clonal process this will have only a minor effect on genotype and allele frequencies in a large cohort. It is likely that this powerful methodology will augment existing techniques in the identification of chromosomal abnormalities.

Pathological tau protein inclusions have long been recognized to define the diverse range of neurodegenerative disorders called the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration. Mutations in the tau gene, MAPT, cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly associated with the risk of PSP, corticobasal degeneration and, to a lesser extent, AD and Parkinson's disease (PD), implicating the involvement of tau in common neurodegenerative pathway(s). This review will discuss recent work towards the unravelling of the functional basis of this MAPT gene association. The region of chromosome 17q21 containing MAPT locus is characterized by the complex genomic architecture, including a large inversion that leads to a bipartite haplotype architecture, an inversion-mediated deletion and multiplications resulting from non-allelic homologous recombination between the MAPT family of low-copy repeats.

Background: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized clinically by resting tremor, bradykinesia, postural instability and rigidity. The prevalence of PD is approximately 2% of the population over 65 years of age and 1.7 million PD patients (age ≥ 55 years) live in China. Recently, a common LRRK2 variant Gly2385Arg was reported in ethnic Chinese PD population in Taiwan. We analyzed the frequency of this variant in our independent PD case-control population of Han Chinese from Taiwan.

The occurrence of epileptic seizures in NF1 patients is related to intracranial tumors but not to NBOs.

Technologies that allow genotyping of more than 100,000 polymorphisms in a single assay enable the execution of genomewide SNP (GWSNP) association studies to identify common genetic variants underlying traits. Less appreciated is the ability of GWSNP assays to map and directly identify rare mutations that cause disease. Here we show the use of this approach in identifying rare structural mutations involved in disease using a large cohort of Parkinson disease (PD) patients and neurologically normal controls by examination of genotype data and copy number metrics. This approach revealed a patient with homozygous mutation at the PARK2 locus. In addition, two heterozygous deletion mutations and five heterozygous duplication mutations within PARK2 were identified in PD subjects and controls. All mutations were confirmed by independent gene dosage experiments. These data demonstrate the utility of this approach in the direct detection of mutations that underlie disease.

Although the magnitude of a genetic component of Parkinson disease (PD [MIM 168600]) remains to be determined, the disease has already shown remarkable genetic heterogeneity, with at least five monogenic forms identified, the most common of which is LRRK2 (MIM 609007). 1 In this issue of The American Journal of Human Genetics, four investigative teams 2-5 report that they have sought to replicate the findings from a genomewide association (GWA) study of PD affection by Maraganore et al. 6 Taken together, these four studies appear to provide substantial evidence that none of the SNPs originally featured as potential PD loci are convincingly replicated and that all may be false positives. Furthermore, that the LRRK2 gene was not identified may be considered a false-negative result. This conclusion is both disappointing and discouraging. The original study invested heavily in this venture, with 443 sibling pairs () discordant for PD typed in tier 1 n p 886 for 198,345 SNPs (172,420,019 genotype calls) and a tier 2 follow-up typing the strongest 1,892 SNPs in 332 matched case-control unrelated pairs (1,176,772 genotypes). Because this report is among the first GWA studies and because the effort appears to have failed to produce the desired objective, it is worth examining the implications for GWA studies in general and, specifically, the significance of this study for PD. First, let's examine the original report. Tier 1 of the original study is founded upon sibling pairs discordant for PD recruited from the Mayo Clinic in Rochester, MN. The sample is composed of individuals substantially of northern and central European descent. Discordant sibling pairs were selected to limit false-positive results due to population stratification bias. 7 Population differences between case and control samples are recognized as the primary source of false-positive associations, and, clearly, every effort to minimize these effects is to be encouraged. However, in PD there is substantial evidence for reduced penetrance, 8 and the disease etiology is most likely a complex interaction of genetic and v77n5/42619/tableS2new.txt and http://www.journals .uchicago.edu/AJHG/journal/issues/v77n5/42619/ tableS3new.txt) in the online-only version of the original article. 6 These results can be readily downloaded and searched for evidence of association with other interesting PD candidate genes. Maraganore and colleagues, with the Michael J. Fox Foundation, have the opportunity to establish a precedent for making the entire GWA study available online, since one may reasonably expect that true PD risk alleles may be found among the SNPs with lesser levels of statistical significance. The jury is still out on whether this GWA study holds important insights for PD.