Genome-wide analysis of the parkinsonism-dementia complex of Guam.
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.


METHODS
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.
Morris
Huw R
HR
Department of Molecular Pathogenesis and Sara Koe PSP Research Centre, Queen Square Brain Bank for Neurological Disorders, Insatitute of Neurology, University College London, London, England, UK.
Steele
John C
JC
Crook
Richard
R
Wavrant-De Vrièze
Fabienne
F
Onstead-Cardinale
Luisa
L
Gwinn-Hardy
Katrina
K
Wood
Nick W
NW
Farrer
Matthew
M
Lees
Andrew J
AJ
McGeer
P L
PL
Siddique
Teepu
T
Hardy
John
J
Perez-Tur
Jordi
J
D000368:Aged; D016009:Chi-Square Distribution; D003704:Dementia / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics*; D015894:Genome, Human; D006141:Guam / Q000453:epidemiology; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000473:pathology; D020734:Parkinsonian Disorders / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree