Dataset Information

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

ABSTRACT: INTRODUCTION:Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated. METHODS:We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid A?42 and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiative study. RESULTS:In CN subjects, study-wide significant (P < 8.3 × 10-9) loci were identified for total tau near SRRM4 and C14orf79 and for hippocampal volume near MTUS1. In mild cognitive impairment subjects, study-wide significant association was found with single nucleotide polymorphisms (SNPs) near ZNF804B for logical memory test of delayed recall scores. We found consistent expression patterns of C14orf40 and MTUS1 in carriers with risk alleles of expression SNPs and in brains of AD patients, compared with in the noncarriers and in brains of controls. DISCUSSION:Our findings for AD-related brain changes before AD provide insight about early AD-related biological processes.

SUBMITTER: Chung J

PROVIDER: S-EPMC5938137 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Chung Jaeyoon J Wang Xulong X Maruyama Toru T Ma Yiyi Y Zhang Xiaoling X Mez Jesse J Sherva Richard R Takeyama Haruko H Lunetta Kathryn L KL Farrer Lindsay A LA Jun Gyungah R GR

Alzheimer's & dementia : the journal of the Alzheimer's Association 20171220 5

<h4>Introduction</h4>Genetic associations for endophenotypes of Alzheimer's disease (AD) in cognitive stages preceding AD have not been thoroughly evaluated.<h4>Methods</h4>We conducted genome-wide association studies for AD-related endophenotypes including hippocampal volume, logical memory scores, and cerebrospinal fluid Aβ<sub>42</sub> and total/phosphorylated tau in cognitively normal (CN), mild cognitive impairment, and AD dementia subjects from the Alzheimer's Disease Neuroimaging Initiati ...[more]

PMID: 29274321

Similar Datasets

Project description:More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (β = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.

Dataset Information

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Publications

Genome-wide association study of Alzheimer's disease endophenotypes at prediagnosis stages.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets