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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 (Aβ 1–42 , t-Tau, p-Tau 181P , t-Tau:Aβ 1–42  ratio, and p-Tau 181P :Aβ 1–42  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 Aβ 1–42  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 Aβ 1–42  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.

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