Human Molecular Genetics, 2003, Vol. 12, No. 1 23-32
© 2003 Oxford University Press
Results of a high-resolution genome screen of 437 Alzheimer's Disease families
1Massachusetts General Hospital, Charlestown, MA, USA, 2University of Alabama at Birmingham, Birmingham, AL, USA, 3Johns Hopkins University, Baltimore, MD, USA and 4Center for Inherited Disease Research, USA
Received July 22, 2002; Accepted November 2, 2002
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 (
4) 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, 6p21, 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.
* To whom correspondence should be addressed at: Genetics and Aging Research Unit, Center for Aging, Genetics and Neurodegeneration, MGH East, 114 16th Street, Charlestown, MA 02129-4404, USA. Tel: +1 6177266845; Fax: +1 6177241949; Email: tanzi{at}helix.mgh.harvard.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Shriner, T. M. Baye, M. A. Padilla, S. Zhang, L. K. Vaughan, and A. E. Loraine Commonality of functional annotation: a method for prioritization of candidate genes from genome-wide linkage studies Nucleic Acids Res., March 27, 2008; 36(4): e26 - e26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Osterfield, R. Egelund, L. M. Young, and J. G. Flanagan Interaction of amyloid precursor protein with contactins and NgCAM in the retinotectal system Development, March 15, 2008; 135(6): 1189 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Patterson MD, J. W. Feightner MD MSc, A. Garcia MD PhD, G.-Y. R. Hsiung MD MHSc, C. MacKnight MD MSc, and A. D. Sadovnick PhD Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease Can. Med. Assoc. J., February 26, 2008; 178(5): 548 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ganguly, R.M. R. Feldman, and M. Guo ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila Hum. Mol. Genet., January 15, 2008; 17(2): 293 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Li, S. Wetten, L. Li, P. L. St. Jean, R. Upmanyu, L. Surh, D. Hosford, M. R. Barnes, J. D. Briley, M. Borrie, et al. Candidate Single-Nucleotide Polymorphisms From a Genomewide Association Study of Alzheimer Disease Arch Neurol, January 1, 2008; 65(1): 45 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Hamshere, P. A. Holmans, D. Avramopoulos, S. S. Bassett, D. Blacker, L. Bertram, H. Wiener, N. Rochberg, R. E. Tanzi, A. Myers, et al. Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer's disease Hum. Mol. Genet., November 15, 2007; 16(22): 2703 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bossu, A. Ciaramella, M. L. Moro, L. Bellincampi, S. Bernardini, G. Federici, A. Trequattrini, F. Macciardi, I. Spoletini, F. Di Iulio, et al. Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer's disease J. Neurol. Neurosurg. Psychiatry, August 1, 2007; 78(8): 807 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. V. De Ferrari, A. Papassotiropoulos, T. Biechele, F. Wavrant De-Vrieze, M. E. Avila, M. B. Major, A. Myers, K. Saez, J. P. Henriquez, A. Zhao, et al. Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease PNAS, May 29, 2007; 104(22): 9434 - 9439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Grupe, R. Abraham, Y. Li, C. Rowland, P. Hollingworth, A. Morgan, L. Jehu, R. Segurado, D. Stone, E. Schadt, et al. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants Hum. Mol. Genet., April 15, 2007; 16(8): 865 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kim, L. B. Hersh, M. A. Leissring, M. Ingelsson, T. Matsui, W. Farris, A. Lu, B. T. Hyman, D. J. Selkoe, L. Bertram, et al. Decreased Catalytic Activity of the Insulin-degrading Enzyme in Chromosome 10-Linked Alzheimer Disease Families J. Biol. Chem., March 16, 2007; 282(11): 7825 - 7832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Bertram, K. Mullin, M. Parkinson, M. Hsiao, T. J Moscarillo, S. L Wagner, K D. Becker, G. Velicelebi, D. Blacker, and R. E Tanzi Is {alpha}-T catenin (VR22) an Alzheimer's disease risk gene? J. Med. Genet., January 1, 2007; 44(1): e63 - e63. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V Giedraitis, M Hedlund, L Skoglund, E Blom, S Ingvast, R Brundin, L Lannfelt, and A Glaser New Alzheimer's disease locus on chromosome 8 J. Med. Genet., December 1, 2006; 43(12): 931 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Lee, R. Cheng, V. Santana, J. Williamson, R. Lantigua, M. Medrano, A. Arriaga, Y. Stern, B. Tycko, E. Rogaeva, et al. Expanded Genomewide Scan Implicates a Novel Locus at 3q28 Among Caribbean Hispanics With Familial Alzheimer Disease Arch Neurol, November 1, 2006; 63(11): 1591 - 1598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Brouwers, K. Sleegers, S. Engelborghs, V. Bogaerts, S. Serneels, K. Kamali, E. Corsmit, E. D. Leenheir, J.-J. Martin, P. P. De Deyn, et al. Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease Brain, November 1, 2006; 129(11): 2984 - 2991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, A. Grupe, C. Rowland, P. Nowotny, J. S.K. Kauwe, S. Smemo, A. Hinrichs, K. Tacey, T. A. Toombs, S. Kwok, et al. DAPK1 variants are associated with Alzheimer's disease and allele-specific expression Hum. Mol. Genet., September 1, 2006; 15(17): 2560 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Riemenschneider, L. Konta, P. Friedrich, S. Schwarz, K. Taddei, F. Neff, A. Padovani, H. Kolsch, S. M. Laws, N. Klopp, et al. A functional polymorphism within plasminogen activator urokinase (PLAU) is associated with Alzheimer's disease Hum. Mol. Genet., August 15, 2006; 15(16): 2446 - 2456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Sebastiani, P. Krzywkowski, S. Dudal, M. Yu, J. Paquette, D. Malo, F. Gervais, and P. Tremblay Mapping genetic modulators of amyloid plaque deposition in TgCRND8 transgenic mice Hum. Mol. Genet., August 1, 2006; 15(15): 2313 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Ramos, M.-T. Lin, E. B. Larson, I. Maezawa, L.-H. Tseng, K. L. Edwards, G. D. Schellenberg, J. A. Hansen, W. A. Kukull, and L.-W. Jin Tumor Necrosis Factor {alpha} and Interleukin 10 Promoter Region Polymorphisms and Risk of Late-Onset Alzheimer Disease. Arch Neurol, August 1, 2006; 63(8): 1165 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Zhang, H. Wiener, M. Beasley, V. George, C. I. Amos, and D. B. Allison An Empirical Bayes Method for Updating Inferences in Analysis of Quantitative Trait Loci Using Information From Related Genome Scans Genetics, August 1, 2006; 173(4): 2283 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. I. Lin, E. R. Martin, P. G. Bronson, C. Browning-Large, G. W. Small, D. E. Schmechel, K. A. Welsh-Bohmer, J. L. Haines, J. R. Gilbert, and M. A. Pericak-Vance Exploring the association of glyceraldehyde-3-phosphate dehydrogenase gene and Alzheimer disease. Neurology, July 11, 2006; 67(1): 64 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Sun, G. He, and W. Song BACE2, as a novel APP {theta}-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome FASEB J, July 1, 2006; 20(9): 1369 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Kuwano, A. Miyashita, H. Arai, T. Asada, M. Imagawa, M. Shoji, S. Higuchi, K. Urakami, A. Kakita, H. Takahashi, et al. Dynamin-binding protein gene on chromosome 10q is associated with late-onset Alzheimer's disease Hum. Mol. Genet., July 1, 2006; 15(13): 2170 - 2182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Erlich, K. L. Lunetta, L. A. Cupples, M. Huyck, R. C. Green, C. T. Baldwin, L. A. Farrer, and for the MIRAGE Study Group Polymorphisms in the PON gene cluster are associated with Alzheimer disease Hum. Mol. Genet., January 1, 2006; 15(1): 77 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L Bertram, M Parkinson, M B McQueen, K Mullin, M Hsiao, R Menon, T J Moscarillo, D Blacker, and R E Tanzi Further evidence for LBP-1c/CP2/LSF association in Alzheimer's disease families J. Med. Genet., November 1, 2005; 42(11): 857 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-A. Bacanu, B. Devlin, K. V. Chowdari, S. T. DeKosky, V. L. Nimgaonkar, and R. A. Sweet Heritability of Psychosis in Alzheimer Disease Am J Geriatr Psychiatry, July 1, 2005; 13(7): 624 - 627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Jimenez-Escrig, E. Gomez-Tortosa, M. Baron, A. Rabano, M. Arcos-Burgos, L. G. Palacios, A. Yusta, P. Anta, I. Perez, M. Hierro, et al. A multigenerational pedigree of late-onset Alzheimer's disease implies new genetic causes Brain, July 1, 2005; 128(7): 1707 - 1715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Slifer, E. R. Martin, J. L. Haines, M. A. Pericak-Vance, L. Bertram, and R. E. Tanzi The Ubiquilin 1 Gene and Alzheimer's Disease N. Engl. J. Med., June 30, 2005; 352(26): 2752 - 2753. [Full Text] [PDF]
|
|
|
|
|
|
A. Diaz-Perales, V. Quesada, L. M. Sanchez, A. P. Ugalde, M. F. Suarez, A. Fueyo, and C. Lopez-Otin Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase J. Biol. Chem., April 8, 2005; 280(14): 14310 - 14317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bertram, M. Hiltunen, M. Parkinson, M. Ingelsson, C. Lange, K. Ramasamy, K. Mullin, R. Menon, A. J. Sampson, M. Y. Hsiao, et al. Family-Based Association between Alzheimer's Disease and Variants in UBQLN1 N. Engl. J. Med., March 3, 2005; 352(9): 884 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Li, P. Nowotny, P. Holmans, S. Smemo, J. S. K. Kauwe, A. L. Hinrichs, K. Tacey, L. Doil, R. van Luchene, V. Garcia, et al. Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family PNAS, November 2, 2004; 101(44): 15688 - 15693. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Krauthammer, C. A. Kaufmann, T. C. Gilliam, and A. Rzhetsky Molecular triangulation: Bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease PNAS, October 19, 2004; 101(42): 15148 - 15153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Iivonen, E. Corder, M. Lehtovirta, S. Helisalmi, A. Mannermaa, S. Vepsalainen, T. Hanninen, H. Soininen, and M. Hiltunen Polymorphisms in the CYP19 gene confer increased risk for Alzheimer disease Neurology, April 13, 2004; 62(7): 1170 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L Bertram, M Parkinson, K Mullin, R Menon, D Blacker, and R E Tanzi No association between a previously reported OLR1 3' UTR polymorphism and Alzheimer's disease in a large family sample J. Med. Genet., April 1, 2004; 41(4): 286 - 288. [Full Text] [PDF]
|
|
|
|
|
|
L. Bertram and R. E. Tanzi Alzheimer's disease: one disorder, too many genes? Hum. Mol. Genet., April 1, 2004; 13(90001): R135 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J-C Lambert, D Mann, J Harris, L Araria-Goumidi, M-C Chartier-Harlin, D Cottel, T Iwatsubo, P Amouyel, and C Lendon Association study of Notch 4 polymorphisms with Alzheimer's disease J. Neurol. Neurosurg. Psychiatry, March 1, 2004; 75(3): 377 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Elkins, V. C. Douglas, and S. C. Johnston Alzheimer disease risk and genetic variation in ACE: A meta-analysis Neurology, February 10, 2004; 62(3): 363 - 368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bertram, R. Menon, K. Mullin, M. Parkinson, M. L. Bradley, D. Blacker, and R. E. Tanzi PEN2 is not a genetic risk factor for Alzheimer's disease in a large family sample Neurology, January 27, 2004; 62(2): 304 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Ma, N. L.S. Tang, L. C.W. Lam, and H. F.K. Chiu Association between tumor necrosis factor-{alpha} promoter polymorphism and Alzheimer's disease Neurology, January 27, 2004; 62(2): 307 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Greenwood and R. Parasuraman Normal Genetic Variation, Cognition, and Aging Behav Cogn Neurosci Rev, December 1, 2003; 2(4): 278 - 306. [Abstract] [PDF]
|
|
|
|
|
|
A. J. Saunders, L. Bertram, K. Mullin, A. J. Sampson, K. Latifzai, S. Basu, J. Jones, D. Kinney, L. MacKenzie-Ingano, S. Yu, et al. Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin Hum. Mol. Genet., November 1, 2003; 12(21): 2765 - 2776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Kennedy, L. A. Farrer, N. C. Andreasen, R. Mayeux, and P. St George-Hyslop The Genetics of Adult-Onset Neuropsychiatric Disease: Complexities and Conundra? Science, October 31, 2003; 302(5646): 822 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J-C Lambert, E Luedecking-Zimmer, S Merrot, A Hayes, U Thaker, P Desai, A Houzet, X Hermant, D Cottel, A Pritchard, et al. Association of 3'-UTR polymorphisms of the oxidised LDL receptor 1 (OLR1) gene with Alzheimer's disease J. Med. Genet., June 1, 2003; 40(6): 424 - 430. [Abstract] [Full Text] [PDF]
|
|