Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers.
Acta Neuropathol
; 133(5): 839-856, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28247064
ABSTRACT
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 (Aß42), 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 Aß42 near GLIS1 on 1p32.3 (ß = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (ß = -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 ß = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1 ß = 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 Aß-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aß42 (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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Proteínas tau
/
Predisposição Genética para Doença
/
Estudo de Associação Genômica Ampla
/
Doença de Alzheimer
Tipo de estudo:
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
/
Aged
/
Aged80
/
Humans
/
Middle aged
Idioma:
En
Revista:
Acta Neuropathol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos