Journal article
Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin
Human molecular genetics, v 12(21), pp 2765-2776
01 Nov 2003
PMID: 12966032
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin
- Creators
- Aleister J. Saunders - Massachusetts General HospitalLars Bertram - Harvard University ,Kristina Mullin - Harvard University ,Andrew J. Sampson - Harvard University ,Khushal Latifzai - Harvard University ,Sanjay Basu - Harvard University ,Jennifer Jones - Harvard University ,Devon Kinney - Harvard University ,Laura MacKenzie-Ingano - Harvard University ,Stephen Yu - Harvard University ,Marilyn S. Albert - Harvard University ,Thomas J. Moscarillo - Harvard University ,Rodney C.P. Go - University of Alabama at BirminghamSusan S. Bassett - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University Medical Institutions, Baltimore, MD, USAMark J. Daly - Whitehead Institute for Biomedical ResearchNan M. Laird - Harvard University ,Xin Wang - NeuroGenetic PharmaceuticalsGonul Velicelebi - NeuroGenetic PharmaceuticalsSteven L. Wagner - NeuroGenetic PharmaceuticalsDavid K. Becker - NeuroGenetic PharmaceuticalsRudolph E. Tanzi - Harvard University ,Deborah Blacker - Harvard University ,
- Publication Details
- Human molecular genetics, v 12(21), pp 2765-2776
- Publisher
- Oxford University Press
- Number of pages
- 12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; DUL Services
- Web of Science ID
- WOS:000186310500004
- Scopus ID
- 2-s2.0-10744226703
- Other Identifier
- 991019173447504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity