title: Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10(-3). The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10(-4)). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan-Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.
authors.affiliation: Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson, TN, USA.
authors.forename: Ke-Sheng
authors.initials: KS
authors.lastname: Wang
authors.forename: Silvina
authors.initials: S
authors.lastname: Tonarelli
authors.forename: Xingguang
authors.initials: X
authors.lastname: Luo
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Brenda
authors.initials: B
authors.lastname: Su
authors.forename: Lingjun
authors.initials: L
authors.lastname: Zuo
authors.forename: ChunXiang
authors.initials: C
authors.lastname: Mao
authors.forename: Lewis
authors.initials: L
authors.lastname: Rubin
authors.forename: David
authors.initials: D
authors.lastname: Briones
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D002170:Canada; D055106:Genome-Wide Association Study; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: C000593289:ASTN2 protein, human; D006023:Glycoproteins; D009419:Nerve Tissue Proteins