Regional Plot for the CSF Aβ_1–42 Loci.

<p><b>(A) <i>FRA10AC1</i> (B) 15q21</b> Association results (-log10 p) are plotted for all single nucleotide polymorphisms (SNPs) passing quality control. Chromosome position is plotted with reference to the NCBI build 37. Recombination rate as estimated from the HapMap Project is plotted in light blue. SNPs are color coded according to the LD measure (r²) with reference SNP based on the reference panel of CEU population from the 1000 Genome Project (March 2012 release). SNP annotation for all 1000GP SNPs are represented by the annotation categories: framestop (triangle), splice (triangle), non-synonymous (inverted triangle), synonymous (square), UTR (square), TFBScons (star), MCS44 Placental (square with diagonal lines) and none-of-the-above (filled circle).</p

Basic demographic information of the three ADNI CSF Sample Sets.

<p>Basic demographic information of the three ADNI CSF Sample Sets.</p

Variations in the <i>FRA10AC1</i> Fragile Site and 15q21 Are Associated with Cerebrospinal Fluid Aβ_1-42 Level

<div><p>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 <i>APOE</i> 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 <i>P</i> < 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 <i>FRA10AC1</i> associated with CSF Aβ_1–42 level passing the genome-wide significance threshold (directly genotyped SNV rs10509663 <i>P</i>_FE = 1.1 x 10⁻⁹, imputed SNV rs116953792 <i>P</i>_FE = 3.5 x 10⁻¹⁰), rs116953792 (<i>P</i>_one-sided = 0.04) achieved replication. This association became stronger in the joint meta-analysis (directly genotyped SNV rs10509663 <i>P</i>_FE = 1.7 x 10⁻⁹, imputed SNV rs116953792 <i>P</i>_FE = 7.6 x 10⁻¹¹). Additionally, we identified locus 15q21 (imputed SNV rs1503351 <i>P</i>_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.</p></div

Inrich Analysis Results (P_corrected < 0.05).

<p>Inrich Analysis Results (P_corrected < 0.05).</p

Summary of cerebral amyloid deposition florbetapir PET quantitative traits—SNPs with uncorrected p-value less than 1x10^-6.

<p>Chr, chromosome; A₁, first allele code; A₂, second allele code</p><p>^a Representative SNPs with uncorrected p < 1x10^-6 in any of the Cerebral amyloid deposition GWAS Analyses</p><p>^b Build 37, assembly hg19</p><p>^c based on 2012 Apr release of 1000genome and all population</p><p>^d Fixed-effects meta-analysis p-value</p><p>^e Beta coefficient of for the SNP assuming additive genetic model</p><p>Top variants were clumped using parameters—clump-p1 0.000001—clump-p2 0.05—clump-r2 0.2—clump-range entrez.gene.map—clump-range-border 20.</p