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Genome-Wide Analysis of the Parkinsonism-Dementia Complex of Guam
Huw R. Morris, MB, PhD;
John C. Steele, MD;
Richard Crook, BSc;
Fabienne Wavrant-De Vrièze, PhD;
Luisa Onstead-Cardinale, BS;
Katrina Gwinn-Hardy, MD;
Nick W. Wood, MD, PhD;
Matthew Farrer, PhD;
Andrew J. Lees, MD;
P. L. McGeer, MD, PhD;
Teepu Siddique, MD, PhD;
John Hardy, PhD;
Jordi Perez-Tur, PhD
Arch Neurol. 2004;61:1889-1897.
Background Parkinsonism-dementia complex (PDC) is a neurofibrillary tangle degeneration involving the deposition of Alzheimer-type tau, predominantly in the mesial temporal cortex, brainstem, and basal ganglia. It occurs in focal geographic isolates, including Guam and the Kii peninsula of Japan. The familial clustering of the disease has suggested that a genetic factor could be important in its etiology.
Objective To determine whether a genetic locus could be identified, linked, or associated with PDC.
Design and Patients We performed a genome-wide association study of 22 Guamanian PDC and 19 control subjects using 834 microsatellite markers with an approximate genome-wide marker density of 4.4 centimorgans.
Results Two-point association analysis identified 17 markers (P<.015). Each of these markers then underwent conventional linkage analysis in 5 families with PDC. One marker, D20S103, generated a logarithm of odds score of greater than 1.5. Multipoint association analysis also highlighted 2 other areas on chromosome 14q (adjacent to D14S592, 59.2 megabases [M]) and chromosome 20 (adjacent to D20S470, 17.4 M) with multipoint association logarithm of the odds scores of greater than 2. The areas around D20S103, D14S592, and D20S470 were further analyzed by association using additional microsatellite markers and by conventional linkage analysis. This did not provide further evidence for the role of these areas in PDC.
Conclusions This study has not identified a single gene locus for PDC, confirming the impression of a geographic disease isolate with a complex genetic, a genetic/environmental etiology, or a purely environmental etiology.
Author Affiliations: Department of Molecular Pathogenesis (Drs Morris, Wood, and Lees) and Sara Koe PSP Research Centre, Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, and Reta Lila Weston Institute of Neurological Sciences, University College London (Drs Morris and Hardy), London, England; Micronesian Health Study II, Tamuning, Guam (Dr Steele); Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Fla (Mr Crook and Drs Wavrant-De Vrièze, Gwinn-Hardy, Hardy, and Perez-Tur); Laboratory of Neurogenetics, National Institute on Aging and National Institute for Neurological Disorders and Stroke, Bethesda, Md (Drs Wavrant-De Vrièze, Gwinn-Hardy, Farrer, and Hardy and Ms Onstead-Cardinale); Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver (Dr McGeer); Department of Neurology, Northwestern University Medical School, Chicago, Ill (Dr Siddique); Unitat de Genètica Molecular, Institut de Biomedicina de València-CSIC, Valencia, Spain (Dr Perez-Tur); and Section of Neurology, Department of Medicine, University of Wales College of Medicine, Cardiff (Dr Morris).
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