title: Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease.
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.
authors.affiliation: Section of Medical Genomics, Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.forename: Laura L
authors.initials: LL
authors.lastname: Kilarski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Maria
authors.initials: M
authors.lastname: Martinez
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Nigel
authors.initials: N
authors.lastname: Williams
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005060:Europe; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D014481:United States