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P4‐164: CNV Regions Profiling and Risk Of Cognitive Impairment in the ADNI Sample
Author(s) -
Macciardi Fabio,
Guffanti Guia,
Torri Federica,
Rasmussen Jerod,
Lakatos Anita,
Turner Jessica A.,
Kruggel Frithjof,
Fallon James H.,
Saykin Andrew,
Weiner Michael,
Potkin Steven
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.08.223
Subject(s) - copy number variation , genotyping , snp , genetics , biology , single nucleotide polymorphism , gene dosage , snp array , genome wide association study , structural variation , snp genotyping , genotype , gene , genome , gene expression
Background: Copy number variations (CNVs), deletions or duplications of DNA segments, represent an important source of the genetic diversity that affects many biological functions. Recently, several studies have provided evidence for a substantial role of chromosomal structural variations in the pathogenesis of neurological disorders (Kalman and Vitale, 2009). This evidence is consistent with the hypothesis that genetic susceptibility to late onset neurodegenerative disorders such as Alzheimer’s disease rely on dosage-sensitive loci directly affected by the functional mechanisms promoted by copy number variations (Blauw et al., 2008). Methods: We present the results from a whole-genome Copy Number Variation (CNV) region study on the 818 subjects collected in the ADNI project. Subjects were genotyped with more than 600,000 SNPs using the Illumina Human610-Quad BeadChip. We identified CNV regions by using Nexus, a CNV calling program that relies on SNP genotyping signal intensities. Results: After both genotyping and CNV quality control procedures, we detected 11,694 CNVs in 638 subjects. The range of frequencies of the CNVs we detected is in accordance with the trend (rarely more than 10%) reported in worldwide control populations (Jacobsson et al., 2008). We identified 10,135 deletions, 1,647 of which are homozygous deletions, and 1,559 duplications, including 6 high copies gain CNVs. We found only one region of overlapping segments homozygously deleted exclusively in MCI subjects. The total number of CNV regions was increased in MCI and AD subjects compared to healthy controls (p < 0.005). Important gene networks and pathways are disrupted by these CNV regions; thus possibly contributing to the pathophysiology of MCI and AD. Conclusions: We present a comprehensive analysis of the structural variants that may contribute to the genetic susceptibility to Mild Cognitive Impairment and Alzheimer’s Disease. The variants primarily include large deletions of .5 to 10-12 Mb many of which disrupt known pathways of biological significance, including CNS axonal development.