Figure 3
(a–d) Manhattan plot of the results of applying a pooling/bootstrap genome-wide association study (pbGWAS) strategy with eight pairs of DNA pools generated from patients from a unique and clinically well-characterized multigenerational pedigree affected by Alzheimer's disease with different ages of onset, all of whom carry the PSEN1 p.Glu280Ala (E280A) mutation. At the y axis, the –log10(P-value) for autosomal single-nucleotide polymorphisms are represented by dots; the x axis corresponds to the genomic coordinates. For display purposes, values in the y axis were smoothed by the median as implemented in Golden Helix. Abbreviations follow the same notation as in Figure 1. Though rs10173717 is ∼20 Kb downstream NPHP1 and ∼2.5 Kb downstream of NCRNA00116, NPHP1 appears to be a better candidate than NCRNA00116 becauseNPHP1 encodes a protein that interacts with PTK2B and BCAR1.44, 45 PTK2B, in turn, encodes a cytoplasmic protein having an important role as intermediate between neuropeptide-activated receptors or as neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity. BCAR1, in turn, is involved in cellular migration, survival, transformation, and invasion.46 Furthermore, the gene-based approach showed that a total of 10 markers inside the NPHP1 gene (chr2: 110 238 202–110 319 928), clustered associated (statistic=177.01, P=2.08 × 10−4). This gene-based association was not present in NCRNA00116.
