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About the Authors:
Dena G. Hernandez
Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
Michael A. Nalls
Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
Pauli Ylikotila
Affiliation: Department of Neurology, Turku University Hospital, Turku, Finland
Margaux Keller
Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
John A. Hardy
Affiliation: Reta Lilla Weston Laboratories and Departments of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, United Kingdom
Kari Majamaa
Affiliation: Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland
Andrew B. Singleton
* E-mail: [email protected]
Affiliation: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
Over the past 15 years the genetic investigation of Parkinson’s disease has successfully identified many disease-causing mutations, and these have been used extensively to understand the etiology of this complex disease. Genome wide association (GWA) studies have been applied to explicitly test the common disease common variant hypothesis in PD [1]. This has led to the identification of a significant number of novel risk loci [2]–[8]. From an etiologic perspective it is notable that some of these loci include genes known to contain mutations that cause neurodegenerative diseases [9].
Within isolated populations, allelic and genetic heterogeneity tends to be reduced and as a result single founder mutations can be quite common in the disease population. Thus the application of GWA in these populations can also lead to the resolution of loci containing highly penetrant mutations, particularly in sub-types of disease that have a substantial monogenic component within conserved populations [10], [11]. Perhaps the best example of this is the description of association at chromosome 9p in a GWA of familial ALS cases from Finland. This ultimately led to the identification of the pathogenic expansion within C9orf72, which causes a substantial number of ALS and frontotemporal dementia cases worldwide [12], [13].
We embarked upon a series of experiments aimed at understanding whether a similar monogenic component may be detectible in PD in the same population. To test this idea we used high content SNP genotyping in a...