title: Genome-wide association analysis of age-at-onset in Alzheimer's disease.
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.
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA. kamboh@pitt.edu
authors: M I
authors: MI
authors: Kamboh
authors: M M
authors: MM
authors: Barmada
authors: F Y
authors: FY
authors: Demirci
authors: R L
authors: RL
authors: Minster
authors: M M
authors: MM
authors: Carrasquillo
authors: V S
authors: VS
authors: Pankratz
authors: S G
authors: SG
authors: Younkin
authors: A J
authors: AJ
authors: Saykin
authors: R A
authors: RA
authors: Sweet
authors: E
authors: E
authors: Feingold
authors: S T
authors: ST
authors: DeKosky
authors: O L
authors: OL
authors: Lopez
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D015820:Cadherins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D015820:Cadherins