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

Aleister J. Saunders, Lars Bertram, Kristina Mullin, Andrew J. Sampson, Khushal Latifzai, Sanjay Basu, Jennifer Jones, Devon Kinney, Laura MacKenzie-Ingano, Stephen Yu, Marilyn Albert, Thomas J. Moscarillo, Rodney C P Go, Susan Bassett, Mark J. Daly, Nan M. Laird, Xin Wang, Gonul Velicelebi, Steven L. Wagner, David K. BeckerRudolph E. Tanzi, Deborah Blacker

Research output: Contribution to journalArticle

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 V10001, 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.

Original languageEnglish (US)
Pages (from-to)2765-2776
Number of pages12
JournalHuman Molecular Genetics
Volume12
Issue number21
DOIs
StatePublished - Nov 1 2003

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alpha-Macroglobulins
Alzheimer Disease
National Institute of Mental Health (U.S.)
Linkage Disequilibrium
Haplotypes
Genes
Case-Control Studies
Chromosomes, Human, Pair 12
Genetic Linkage
National Institutes of Health (U.S.)

ASJC Scopus subject areas

  • Genetics

Cite this

Saunders, A. J., Bertram, L., Mullin, K., Sampson, A. J., Latifzai, K., Basu, S., ... Blacker, D. (2003). Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin. Human Molecular Genetics, 12(21), 2765-2776. https://doi.org/10.1093/hmg/ddg310

Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin. / Saunders, Aleister J.; Bertram, Lars; Mullin, Kristina; Sampson, Andrew J.; Latifzai, Khushal; Basu, Sanjay; Jones, Jennifer; Kinney, Devon; MacKenzie-Ingano, Laura; Yu, Stephen; Albert, Marilyn; Moscarillo, Thomas J.; Go, Rodney C P; Bassett, Susan; Daly, Mark J.; Laird, Nan M.; Wang, Xin; Velicelebi, Gonul; Wagner, Steven L.; Becker, David K.; Tanzi, Rudolph E.; Blacker, Deborah.

In: Human Molecular Genetics, Vol. 12, No. 21, 01.11.2003, p. 2765-2776.

Research output: Contribution to journalArticle

Saunders, AJ, Bertram, L, Mullin, K, Sampson, AJ, Latifzai, K, Basu, S, Jones, J, Kinney, D, MacKenzie-Ingano, L, Yu, S, Albert, M, Moscarillo, TJ, Go, RCP, Bassett, S, Daly, MJ, Laird, NM, Wang, X, Velicelebi, G, Wagner, SL, Becker, DK, Tanzi, RE & Blacker, D 2003, 'Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin', Human Molecular Genetics, vol. 12, no. 21, pp. 2765-2776. https://doi.org/10.1093/hmg/ddg310
Saunders AJ, Bertram L, Mullin K, Sampson AJ, Latifzai K, Basu S et al. Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin. Human Molecular Genetics. 2003 Nov 1;12(21):2765-2776. https://doi.org/10.1093/hmg/ddg310
Saunders, Aleister J. ; Bertram, Lars ; Mullin, Kristina ; Sampson, Andrew J. ; Latifzai, Khushal ; Basu, Sanjay ; Jones, Jennifer ; Kinney, Devon ; MacKenzie-Ingano, Laura ; Yu, Stephen ; Albert, Marilyn ; Moscarillo, Thomas J. ; Go, Rodney C P ; Bassett, Susan ; Daly, Mark J. ; Laird, Nan M. ; Wang, Xin ; Velicelebi, Gonul ; Wagner, Steven L. ; Becker, David K. ; Tanzi, Rudolph E. ; Blacker, Deborah. / Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 21. pp. 2765-2776.
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AU - Latifzai, Khushal

AU - Basu, Sanjay

AU - Jones, Jennifer

AU - Kinney, Devon

AU - MacKenzie-Ingano, Laura

AU - Yu, Stephen

AU - Albert, Marilyn

AU - Moscarillo, Thomas J.

AU - Go, Rodney C P

AU - Bassett, Susan

AU - Daly, Mark J.

AU - Laird, Nan M.

AU - Wang, Xin

AU - Velicelebi, Gonul

AU - Wagner, Steven L.

AU - Becker, David K.

AU - Tanzi, Rudolph E.

AU - Blacker, Deborah

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N2 - 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 V10001, 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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