Human Molecular Genetics Advance Access originally published online on June 30, 2009
Human Molecular Genetics 2009 18(19):3725-3738; doi:10.1093/hmg/ddp300
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Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates
1 Division of Medical Genetics, Department of Medicine, 2 Department of Biostatistics, 3 Department of Neurology, 4 Division of Gerontology and Geriatric Medicine, Department of Medicine, 5 Department of Pharmacology and 6 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA, 7 Division of Epidemiology, Department of Health Research and Policy, Stanford University, Stanford, CA 94305, USA, 8 Micronesian Health and Aging Study, University of Guam, Mangilao, Guam 96923, USA, 9 Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108, USA, 10 Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan, 11 Laboratory of Biomedical Anthropology and Neurosciences, Department of Anthropology, Binghamton University, Binghamton, NY 13902, USA, 12 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA and 13 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
* To whom correspondence should be addressed at: Division of Medical Genetics, University of Washington, Box 357720, Seattle, WA 98195-7720, USA. Tel: +1 2065438987; Fax: +1 2066161973; Email: wijsman{at}u.washington.edu
Received April 22, 2009; Revised June 17, 2009; Accepted June 25, 2009
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, Zmax = 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 (Zmax = 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.