title: Variations in the FRA10AC1 Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ1-42 Level.
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 PFE = 1.1 x 10-9, imputed SNV rs116953792 PFE = 3.5 x 10-10), rs116953792 (Pone-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 PFE = 1.7 x 10-9, imputed SNV rs116953792 PFE = 7.6 x 10-11). Additionally, we identified locus 15q21 (imputed SNV rs1503351 PFE = 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.
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States of America.
authors.forename: Qingqin S
authors.initials: QS
authors.lastname: Li
authors.affiliation: Discovery Science, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19002, United States of America.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Parrado
authors.affiliation: Clinical Pharmacology, Advanced PK/PD Modeling and Simulation, Janssen Research & Development, LLC, 920 Route 202, Raritan, NJ 08869, United States of America.
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, LLC, 1125 Trenton-Harbourton Road, Titusville, NJ 08560, United States of America.
authors.forename: Vaibhav A
authors.initials: VA
authors.lastname: Narayan
mesh_terms: D000368:Aged; D000682:Amyloid / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D043283:Chromosome Fragile Sites / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049268:Positron-Emission Tomography
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; C496403:FRA10AC1 protein, human; D009687:Nuclear Proteins