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Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease

Simon-Sanchez, J; Kilarski, LL; Nalls, MA; Martinez, M; Schulte, C; Holmans, P; Gasser, T; ... Consor, WTCC; + view all (2012) Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease. PLOS ONE , 7 (3) , Article e28787. 10.1371/journal.pone.0028787. Green open access

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Abstract

Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis

Type: Article
Title: Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0028787
Publisher version: http://dx.doi.org/10.1371/journal.pone.0028787
Language: English
Additional information: This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. This work was supported by the Medical Research Council UK (G0700943) and Parkinson's UK (Grant 8047 and J-0804). This work was supported in part by the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000949-05. This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. Additionally, part of the study was undertaken at UCLH/UCL using funding through a Department of Health NIHR Biomedical Research Centre. We used genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson's disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. The WTCCC2 project was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z); the authors acknowledge use of the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). The authors also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam, and the Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) for sponsoring this work. The KORA research platform (KORA: Cooperative Research in the Region of Augsburg; http://www.gsf.de/KORA) was initiated and financed by the Forschungszentrum für Umwelt und Gesundheit (GSF), which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research), and by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468), and in the frame of ERA-Net NEURON (01GW0908). This work was also supported by the Helmholtz Alliance Mental Health in an Ageing Society (HelMA, HA-215) funded by the Initiative and Networking Fund of the Helmholtz Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1346529
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