TY - JOUR
T1 - Results of a high-resolution genome screen of 437 Alzheimer's Disease families
AU - Blacker, Deborah
AU - Bertram, Lars
AU - Saunders, Aleister J.
AU - Moscarillo, Thomas J.
AU - Albert, Marilyn S.
AU - Wiener, Howard
AU - Perry, Rodney T.
AU - Collins, Julianne S.
AU - Harrell, Lindy E.
AU - Go, Rodney C.P.
AU - Mahoney, Amy
AU - Beaty, Terri
AU - Fallin, M. Danielle
AU - Avramopoulos, Dimitrios
AU - Chase, Gary A.
AU - Folstein, Marshal F.
AU - Mcinnis, Melvin
AU - Bassett, Susan S.
AU - Doheny, Kimberly J.
AU - Pugh, Elizabeth
AU - Tanzi, Rudolph E.
N1 - Funding Information:
The authors thank all families for their participation, Drs Nan M. Laird and Ellen Wijsman for advice regarding statistical methodology, and Dr Steven Moldin and staff at NIMH and all three sites for assistance with all aspects of the project. This work was sponsored by grants from the NIMH and the National Institute on Aging. L.B. was a fellow of the Deutsche Forschungsgemeinschaft and is now recipient of a translational research fellowship of the Harvard Center for Neurodegeneration and Repair. A.J.S. was an NIA-NRSA recipient. Data and biomaterials were collected in three projects that participated in the National Institute of Mental Health (NIMH) Alzheimer Disease Genetics Initiative. From 1991–1998, the Principal Investigators and Co-Investigators were: Massachusetts General Hospital, Boston, MA, U01 MH46281, M.S.A and D.B.; Johns Hopkins University, Baltimore, MD, U01 MH46290, S.S.B., G.A.C. and M.F.F.; University of Alabama, Birmingham, AL, U01 MH46373, R.C.P.G. and L.E.H. Genotyping services were provided by the Center for Inherited Disease Research (CIDR), which is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403.
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (ε4) in the gene encoding apolipoprotein E (APOE) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations - on 1q23, 3p26, 4q32, 5p14, 6p2l, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22 - met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS)≥1.9 and/or multipoint lod score (MLS) ≥ 2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (ε4) in the gene encoding apolipoprotein E (APOE) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations - on 1q23, 3p26, 4q32, 5p14, 6p2l, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22 - met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS)≥1.9 and/or multipoint lod score (MLS) ≥ 2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
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U2 - 10.1093/hmg/ddg007
DO - 10.1093/hmg/ddg007
M3 - Review article
C2 - 12490529
AN - SCOPUS:12244296117
SN - 0964-6906
VL - 12
SP - 23
EP - 32
JO - Human molecular genetics
JF - Human molecular genetics
IS - 1
ER -