Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates.
Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.
Sieh
Weiva
W
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Choi
Yoonha
Y
Chapman
Nicola H
NH
Craig
Ulla-Katrina
UK
Steinbart
Ellen J
EJ
Rothstein
Joseph H
JH
Oyanagi
Kiyomitsu
K
Garruto
Ralph M
RM
Bird
Thomas D
TD
Galasko
Douglas R
DR
Schellenberg
Gerard D
GD
Wijsman
Ellen M
EM
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006141:Guam; D006801:Humans; D008297:Male; D008875:Middle Aged; D044468:Native Hawaiian or Pacific Islander / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010375:Pedigree; D055815:Young Adult