SCIENCE@home

Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ1-42 Level

Qingqin S. Li,A. Parrado,M. Samtani,V. Narayan

Published 2015 in PLoS ONE

ABSTRACT

Proteolytic fragments of amyloid and post-translational modification of tau species in Cerebrospinal fluid (CSF) as well as cerebral amyloid deposition are important biomarkers for Alzheimer’s Disease. We conducted genome-wide association study to identify genetic factors influencing CSF biomarker level, cerebral amyloid deposition, and disease progression. The genome-wide association study was performed via a meta-analysis of two non-overlapping discovery sample sets to identify genetic variants other than APOE ε4 predictive of the CSF biomarker level (Aβ1–42, t-Tau, p-Tau181P, t-Tau:Aβ1–42 ratio, and p-Tau181P:Aβ1–42 ratio) in patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Loci passing a genome-wide significance threshold of P < 5 x 10−8 were followed-up for replication in an independent sample set. We also performed joint meta-analysis of both discovery sample sets together with the replication sample set. In the discovery phase, we identified variants in FRA10AC1 associated with CSF Aβ1–42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 P FE = 1.1 x 10−9, imputed SNV rs116953792 P FE = 3.5 x 10−10), rs116953792 (P one-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 P FE = 1.7 x 10−9, imputed SNV rs116953792 P FE = 7.6 x 10−11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 P FE = 4.0 x 10−8) associated with CSF Aβ1–42 level. No other variants passed the genome-wide significance threshold for other CSF biomarkers in either the discovery sample sets or joint analysis. Gene set enrichment analyses suggested that targeted genes mediated by miR-33, miR-146, and miR-193 were enriched in various GWAS analyses. This finding is particularly important because CSF biomarkers confer disease susceptibility and may be predictive of the likelihood of disease progression in Alzheimer’s Disease.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-41 of 41 references · Page 1 of 1

CITED BY

Showing 1-46 of 46 citing papers · Page 1 of 1