title: Genetic association of Alzheimer's disease with multiple polymorphisms in alpha-2-macroglobulin.
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.
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Aleister J
authors.initials: AJ
authors.lastname: Saunders
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Kristina
authors.initials: K
authors.lastname: Mullin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sampson
authors.forename: Khushal
authors.initials: K
authors.lastname: Latifzai
authors.forename: Sanjay
authors.initials: S
authors.lastname: Basu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jones
authors.forename: Devon
authors.initials: D
authors.lastname: Kinney
authors.forename: Laura
authors.initials: L
authors.lastname: MacKenzie-Ingano
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Albert
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Moscarillo
authors.forename: Rodney C P
authors.initials: RC
authors.lastname: Go
authors.forename: Susan S
authors.initials: SS
authors.lastname: Bassett
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Nan M
authors.initials: NM
authors.lastname: Laird
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Gonul
authors.initials: G
authors.lastname: Velicelebi
authors.forename: Steven L
authors.initials: SL
authors.lastname: Wagner
authors.forename: David K
authors.initials: DK
authors.lastname: Becker
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*; D000511:alpha-Macroglobulins / Q000235:genetics*
chemical_list: D000511:alpha-Macroglobulins