Rare copy number variation in the GR@ACE/DEGESCO dementia dataset of spanish population

Abstract

AbstractBackgroundRecent studies have found that duplications or deletions of DNA fragments, known as copy number variants (CNVs), may play a role in missing heritability for complex human diseases.MethodIn that sense, we conducted a scan for CNVs in the GR@ACE/DEGESCO dementia dataset of Spanish population1 (n = 20,080 individuals using Axiom 815K Spanish biobank array (Thermo Fisher)). We ran CNV calling algorithms from PennCNV software to obtain high‐confidence calls for CNVs. After extensive quality control (QC) for individuals (sex discrepancies, excess of heterozygosity, high missingness, familiar relations and population outliers were excluded), CNVs (>50kb and nSNPs>10 were included), removing spurious CNVs in telomeric/centromeric regions, gene QC (ANOVA comparisons between DNA origin source evaluated in controls), 8,275 controls and 7,818 dementia cases were selected for following analysis.ResultGlobal burden analyses revealed highly significant differences between dementia cases and controls (dem/ctrl) in CNV rate of deletions (p = 2.69E‐04, meanctrl‐dem = 1.53‐1.38) but not in duplications (p = 0.535, meanctrl‐dem = 1.63‐1.61). However, only the number of genes affected by CNVs was significantly different in deletions (p = 0.042, meanctrl‐dem = 3.62‐3.10; duplications p = 0.448, meanctrl‐dem = 5.93‐5.68). We also observed a nominal deletion‐gene‐affected association by genes related to nervous system development pathway or intellectual disability such as VPS13B2 (nine cases affected), PKP3 (Freqctrl‐dem 0.17‐0.25%) and FBRSL13 (Freqctrl‐dem 0.15‐0.26%). The current study did not detect significant differences in CNVs that affect known Alzheimer’s disease (AD) loci identified by recent genome‐wide association studies4 (deletions Fisher test p = 0.0875, duplications Fisher Test p = 0.5853). Nevertheless, we found three important AD genes with CNVs potentially associated to dementia. Specifically, we detected MAPT protective deletions (Freqctrl‐dem 0.16‐0.01%), ABCA7 risk deletions (Freqctrl‐dem 0.05‐0.14%) and APP CNVs detected in five dementia cases (0.064%). Because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia.ConclusionWe have detected potential CNVs in the Spanish population for Alzheimer’s disease, however, because the technology used in our study has limitations in detecting small CNVs, future studies must carefully assess the presence of smaller CNVs and their relationship with dementia.