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. 2018;45(1-2):1-17.
doi: 10.1159/000485503. Epub 2018 Feb 27.

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Free PMC article

Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Elizabeth E Blue et al. Dement Geriatr Cogn Disord. .
Free PMC article


Background/aims: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer's disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP.

Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as "pathogenic" in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations.

Results/conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.

Keywords: Alzheimer genetics; Alzheimer’s disease; Arylsulfatase A pseudodeficiency; Candidate genes; ClinVar; Frontotemporal dementia; Pathogenicity; Rare variants.

Conflict of interest statement

Conflicts of Interest

All authors declare no conflicts of interest.


Figure 1
Figure 1. Distribution of consequential ClinVar SNVs across dementia genes
Y axis = number of pathogenic/likely pathogenic/risk variant/protective variants meeting inclusion criteria. Black: missense variants, white: start or stop gain or loss or frameshift, dark grey: splice donor/acceptor/region variant, light grey: 3’UTR variant.
Figure 2
Figure 2. Percent of SNVs passing pathogenic/deleterious/conserved thresholds across SNV data sets
PolyPhen2: 143/496 SNVs were missing data, SIFT scores: 116/496 SNVs were missing data, phred-scaled CADD scores: 85/496 were missing data, GERP scores: 85/496 SNVs are missing data. Black: All consequential variants in 1000 genomes, dark grey = consequential variants in 1000 genomes with minor allele frequency < 0.001 in 1000 Genomes, Exome Sequencing Project, and Exome Aggregation Consortium data sets, white: consequential variants reported in ClinVar, light grey: consequential variants in CPD controls.

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