Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease
Year: 2012
Type: article
Study design: Observational Study
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.
Source: PLoS ONE
Institutions: Amsterdam UMC Location Vrije Universiteit Amsterdam, Cardiff University, National Institutes of Health, National Institute on Aging, Université Toulouse III - Paul Sabatier, Inserm, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, UCL Queen Square Institute of Neurology, University College London, Centre National de la Recherche Scientifique, Institut du Cerveau, Université Pierre-et-Marie-Curie
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: U.S. Department of Health and Human Services, University of Dundee, Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, Parkinson's UK, University of Sheffield, Cardiff University, University of Bristol, Institut National de la Santé et de la Recherche Médicale, Vrije Universiteit Amsterdam, Bundesministerium für Bildung und Forschung, Hersenstichting, University College London Hospitals NHS Foundation Trust, National Institutes of Health, Medical Research Council, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: WTCCC2 core activities., G1137313802, G1859083642, WTCCC2 core activities, Verbundprojekt: Nationales Genomforschungsnetz 2: Systematisch-Methodische Plattform GEM: Standort Kiel: PopGen: Populationsrepräsentative Biobank Schleswig-Holstein, G2824707892, G2845388095, G2953502109, G3327757157, G3349769430, G4265316335, Verbundprojekt Funktionelle Genomik der Parkinson-Erkrankung : Genomik, funktionelle Analyse und Bioinformatik (Teilprojekt 1, TP2, TP8, TP9, TP10, TP12, TP16), G5502349062, G5568298347, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, G6265045657, G6661414329, G6804723138, G690763772, G695839759, WTCCC2 core activities., G7310981802, Genome wide SNP analysis in Parkinson's disease, A systematic investigation into the pathogenesis and course of Parkinson's syndrome.
OpenAlex ID: W2106199220