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Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer’s disease

  • Neurology and Preclinical Neurological Studies - Original Article
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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.

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Acknowledgments

This work was supported in part by National Institute on Drug Abuse (NIDA) grant K01 DA029643, National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants R21 AA021380 and R21 AA020319, the National Alliance for Research on Schizophrenia and Depression (NARSAD) Award 17616 (L.Z.) and ABMRF/The Foundation for Alcohol Research (L.Z.). We acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study, and the primary funding organization that supported the contributing study “National Institute on Aging (NIA) Late-Onset Alzheimer’s Disease Genetics Initiative: The Multiplex Family Study”. The NIA dataset used for analyses described in this manuscript was obtained from dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000160.v1.p1 through dbGaP accession number: phs000160.v1.p1. Funding support for the “Genetic Consortium for Late-Onset Alzheimer’s Disease” was provided through the Division of Neuroscience, NIA. The Genetic Consortium for Late-Onset Alzheimer’s Disease includes a genome-wide association study funded as part of the Division of Neuroscience, NIA. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by Genetic Consortium for Late-Onset Alzheimer’s Disease. We also acknowledge the NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype data and DNA samples from his/her original study and the primary funding organization that supported the contributing study “Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s disease and longitudinal follow-up of Genotype-Phenotype Associations in Alzheimer’s disease and Neuroimaging component of Genotype-Phenotype Associations in Alzheimer’s disease”. The genotypic and associated phenotypic data used in the study, “Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer’s Disease (GenADA)” were provided by the GlaxoSmithKline, R&D Limited. The datasets used for analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000219.v1.p1.

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Authors and Affiliations

  1. Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson, TN, USA

    Ke-Sheng Wang & Liang Wang

  2. Departments of Psychiatry, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    Silvina Tonarelli & David Briones

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Xingguang Luo & Lingjun Zuo

  4. Colleges of Bioinformatics Science and Technology, Harbin Medical University, Harbin, HeiLongJing, China

    Brenda Su

  5. Department of Pediatrics, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA

    ChunXiang Mao, Lewis Rubin & Chun Xu

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  1. Ke-Sheng Wang
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  2. Silvina Tonarelli
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  10. Chun Xu
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Correspondence to Chun Xu.

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Wang, KS., Tonarelli, S., Luo, X. et al. Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer’s disease. J Neural Transm 122, 701–708 (2015). https://doi.org/10.1007/s00702-014-1306-z

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  • DOI: https://doi.org/10.1007/s00702-014-1306-z

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