title: Gene-based aggregate SNP associations between candidate AD genes and cognitive decline.
abstract: Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions BIN1, CD33, CELF1, CR1, HLA cluster, and MEF2C in the all-female cohort and significant associations with ABCA7, HLA cluster, MS4A6E, PICALM, PTK2B, SLC24A4, and SORL1 in the all-male cohort. We also identified a block of eight correlated SNPs in CD33 and several blocks of correlated SNPs in CELF1 that were significantly associated with cognitive decline in univariate analysis in the all-female cohort.
authors.affiliation: Department of Psychiatry, University of San Francisco - California, 4150 Clement Street, Box VAMC-116H, San Francisco, CA, 94121, USA. jasminen@gmail.com.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Nettiksimmons
authors.affiliation: California Pacific Medical Center Research Institute, Department of Epidemiology and Biostatistics, University of California - San Francisco, Mission Hall: Global Health & Clinical Sciences Building, 550 16th Street, 2nd floor, Box #0560, San Francisco, CA, 94158-2549, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Tranah
authors.affiliation: California Pacific Medical Center Research Institute, Mission Hall: Global Health & Clinical Sciences Building, 550 16th Street, 2nd floor, Box #0560, San Francisco, CA, 94158-2549, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Memory and Aging Center, University of California - San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.affiliation: Departments of Psychiatry, Neurology, and Epidemiology and Biostatistics, University of California - San Francisco, San Francisco Veterans Affairs Medical Center, 4150 Clement Street, Box 181, San Francisco, CA, 94121, USA.
authors.forename: Kristine
authors.initials: K
authors.lastname: Yaffe
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics*; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D004247:DNA
keywords: Candidate AD genes; Cognitive decline; SNP associations