Genome-wide association analysis of age-at-onset in Alzheimer's disease.

TitleGenome-wide association analysis of age-at-onset in Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2012
AuthorsKamboh, MI, Barmada, MM, Demirci, FY, Minster, RL, Carrasquillo, MM, Pankratz, VS, Younkin, SG, Saykin, AJ, Sweet, RA, Feingold, E, DeKosky, ST, Lopez, OL
Corporate AuthorsAlzheimer's Disease Neuroimaging Initiative
JournalMol Psychiatry
Volume17
Issue12
Pagination1340-6
Date Published2012 Dec
ISSN1476-5578
KeywordsAge of Onset, Aged, Alzheimer Disease, Apolipoproteins E, Cadherins, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide
Abstract

The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ~2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.

DOI10.1038/mp.2011.135
Alternate JournalMol. Psychiatry
PubMed ID22005931
PubMed Central IDPMC3262952
Grant ListK01 AG030514 / AG / NIA NIH HHS / United States
R01 AG019771 / AG / NIA NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
P50 AG005133-28 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
R01 AG027224-05 / AG / NIA NIH HHS / United States
RC2 AG036535 / AG / NIA NIH HHS / United States
AG18023 / AG / NIA NIH HHS / United States
R01 AG018023-05 / AG / NIA NIH HHS / United States
AG030653 / AG / NIA NIH HHS / United States
R01 AG030653-03 / AG / NIA NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
R01 AG19771 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG027224 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
AG005133 / AG / NIA NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
AG027224 / AG / NIA NIH HHS / United States