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Human Molecular Genetics Advance Access originally published online on September 9, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 21 2765-2776
DOI: 10.1093/hmg/ddg310
© 2003 Oxford University Press

Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin

Aleister J. Saunders1,{dagger},{ddagger}, Lars Bertram1,{dagger}, Kristina Mullin1, Andrew J. Sampson1, Khushal Latifzai1, Sanjay Basu1, Jennifer Jones1, Devon Kinney1, Laura MacKenzie-Ingano1, Stephen Yu1, Marilyn S. Albert2,3, Thomas J. Moscarillo3, Rodney C.P. Go4, Susan S. Bassett5, Mark J. Daly6, Nan M. Laird7, Xin Wang8, Gonul Velicelebi8, Steven L. Wagner8, David K. Becker8, Rudolph E. Tanzi1,* and Deborah Blacker3,9

1Genetics and Aging Research Unit, Center for Aging, Genetics, and Neurodegeneration, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA, 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA, 3Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA, 4Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL, USA, 5Department of Psychiatry and Behavioral Sciences, Johns Hopkins University Medical Institutions, Baltimore, MD, USA, 6Whitehead Institute for Biomedical Research, Cambridge, MA, USA, 7Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 8Neurogenetics Inc., La Jolla, CA, USA and 9Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

Received June 12, 2003; Accepted August 28, 2003

Alpha-2-Macroglobulin (A2M) is a highly plausible candidate gene for Alzheimer's disease (AD) in a region of chromosome 12 that has numerous independent reports of genetic linkage. We previously reported that a 5 bp deletion in A2M was associated with AD in a subset of the National Institute of Health (NIMH) Genetics Initiative AD family sample. Efforts to replicate this association finding in case – control samples have been largely negative, while those in family samples have been more positive. We hypothesized that variable findings regarding this deletion, along with variable reports of association with V1000I, another polymorphism in the gene, result from linkage disequilibrium in the area as well as ascertainment differences between family-based and case–control studies. Thus, we resequenced the A2M locus to identify novel polymorphisms to test for genetic association with AD. We identified seven novel polymorphisms and tested them in the full NIMH sample of 1439 individuals in 437 families. We found significant genetic association of the 5 bp deletion and two novel polymorphisms with AD. Substantial linkage disequilibrium was detected across the gene as a whole, and haplotype analysis also showed significant association between AD and groups of A2M polymorphisms. Several of these polymorphisms and haplotypes remain significantly associated with AD even after correction for multiple testing. Taken together, these findings, and the positive reports in other family-based studies, continue to support a potential role for A2M or a nearby gene in AD. However, the negative case – control studies suggest that any underlying pathogenic polymorphisms have a modest effect, and may operate primarily among individuals with a family history of AD.

* To whom correspondence should be addressed at: Genetics and Aging Research Unit, C3809, 114 16th St, Charlestown, MA 02129, USA. Tel: +1 617 726 6845; Fax: +1 617 724 1823; Email: tanzi{at}helix.mgh.harvard.edu

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address: Department of Bioscience and Biotechnology, Drexel University, 3141 Chestnut St, Philadelphia, PA 19104, USA.


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