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

被引:59
作者
Saunders, AJ
Bertram, L
Mullin, K
Sampson, AJ
Latifzai, K
Basu, S
Jones, J
Kinney, D
MacKenzie-Ingano, L
Yu, S
Albert, MS
Moscarillo, TJ
Go, RCP
Bassett, SS
Daly, MJ
Laird, NM
Wang, X
Velicelebi, G
Wagner, SL
Becker, DK
Tanzi, RE
Blacker, D
机构
[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Genet & Aging Res Unit, Dept Neurol,Ctr Aging Genet & Neurodegenerat, Charlestown, MA 02129 USA
[2] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Gerontol Res Unit, Charlestown, MA USA
[3] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA
[4] Johns Hopkins Univ, Inst Med, Dept Psychiat & Behav Sci, Baltimore, MD USA
[5] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[6] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA
[7] Neurogenet Inc, La Jolla, CA USA
[8] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA
关键词
D O I
10.1093/hmg/ddg310
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2765 / 2776
页数:12
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