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Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's Disease

Simón-Sánchez, Javier, Kilarski, Laura, Nalls, Michael A., Martinez, Maria, Schulte, Claudia, Holmans, Peter Alan ORCID: https://orcid.org/0000-0003-0870-9412, Gasser, Thomas, Hardy, John, Singleton, Andrew B., Wood, Nicholas W., Brice, Alexis, Heutink, Peter, Williams, Nigel Melville ORCID: https://orcid.org/0000-0003-1177-6931 and Morris, Huw Rees 2012. Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's Disease. PLoS ONE 7 (3) , e28787. 10.1371/journal.pone.0028787

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Systems Immunity Research Institute (SIURI)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Publisher: PLoS
ISSN: 1932-6203
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 May 2023 01:03
URI: https://orca.cardiff.ac.uk/id/eprint/43114

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