Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.

TitleGenome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.
Publication TypeJournal Article
Year of Publication2009
AuthorsBeecham GW, Martin ER, Li Y-J, Slifer MA, Gilbert JR, Haines JL, Pericak-Vance MA
JournalAm J Hum Genet
Volume84
Issue1
Pagination35-43
Date Published2009 Jan
ISSN1537-6605
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Chromosomes, Human, Pair 12, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk
Abstract

Only Apolipoprotein E polymorphisms have been consistently associated with the risk of late-onset Alzheimer disease (LOAD), but they represent only a minority of the underlying genetic effect. To identify additional LOAD risk loci, we performed a genome-wide association study (GWAS) on 492 LOAD cases and 498 cognitive controls using Illumina's HumanHap550 beadchip. An additional 238 cases and 220 controls were used as a validation data set for single-nucleotide polymorphisms (SNPs) that met genome-wide significance. To validate additional associated SNPs (p < 0.0001) and nominally associated candidate genes, we imputed SNPs from our GWAS using a previously published LOAD GWAS(1) and the IMPUTE program. Association testing was performed with the Cochran-Armitage trend test and logistic regression, and genome-wide significance was determined with the False Discovery Rate-Beta Uniform Mixture method. Extensive quality-control methods were performed at both the sample and the SNP level. The GWAS confirmed the known APOE association and identified association with a 12q13 locus at genome-wide significance; the 12q13 locus was confirmed in our validation data set. Four additional highly associated signals (1q42, 4q28, 6q14, 19q13) were replicated with the use of the imputed data set, and six candidate genes had SNPs with nominal association in both the GWAS and the joint imputated data set. These results help to further define the genetic architecture of LOAD.

DOI10.1016/j.ajhg.2008.12.008
Alternate JournalAm. J. Hum. Genet.
PubMed ID19118814
PubMed Central IDPMC2668056
Grant ListAG19757 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 NS031153 / NS / NINDS NIH HHS / United States
R01 AG019757-06 / AG / NIA NIH HHS / United States
NS31153 / NS / NINDS NIH HHS / United States
R01 AG020135 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
R01 AG027944-01A2 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
AG20135 / AG / NIA NIH HHS / United States