Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

SummaryPrevious studies have implicated common and rare genetic variants as risk factors for late onset Alzheimer’s disease (AD, LOAD). Here, weighted burden analysis was applied to over 10,000 exome sequenced subjects from the Alzheimer’s Disease Sequencing Project. Analyses were carried out to investigate whether rare variants predicted to have a functional effect within a gene were more commonly seen in cases or in controls. Confirmatory results were obtained for TREM2, ABCA7 and SORL1. Additional support was provided for PSEN1 (p = 0.0002), which previously had been only weakly implicated in LOAD. There was suggestive evidence that functional variants in PIK3R1, WNT7A, C1R and EXOC5 might increase risk and that variants in TIAF1 and/or NDRG2 might have a protective effect. Overall, there was strong evidence (p = 5 × 10−6) that variants in tyrosine phosphatase genes reduce the risk of developing LOAD. Since PIK3R1 variants are expected to impair PI3K/Akt/GSK-3β signalling while variants in tyrosine phosphatase genes would enhance it, these findings are in line with those from animal models suggesting that this pathway is protective against AD.

Download Full-text

Correction: Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families

PLoS ONE ◽

10.1371/annotation/c92e16da-7733-421d-b063-1db19488daa6 ◽

2012 ◽

Vol 7 (5) ◽

Cited By ~ 18

Author(s):

Carlos Cruchaga ◽

Sumitra Chakraverty ◽

Kevin Mayo ◽

Francesco L. M. Vallania ◽

Robi D. Mitra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Increase Risk

Download Full-text

Genetic Analysis of TREM2 Variants in Tunisian Patients with Alzheimer's Disease

Medical Principles and Practice ◽

10.1159/000489779 ◽

2018 ◽

Vol 27 (4) ◽

pp. 317-322 ◽

Cited By ~ 1

Author(s):

Zied Landoulsi ◽

Mouna Ben Djebara ◽

Imen Kacem ◽

Youssef Sidhom ◽

Rym Kefi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Tunisian Population ◽

Fisher Exact Test ◽

Exon 2 ◽

Exact Test ◽

Tunisian Patients ◽

Synonymous Variant

Objective: Rare variants in the TREM2 gene have been reported to significantly increase the risk of Alzheimer’s disease in Caucasian populations. Hitherto, this association was not studied in North African populations. In this work, we aimed to study the association between TREM2 exon 2 variants and the risk of late-onset Alzheimer’s disease (LOAD) in a Tunisian population. Subjects and Methods: We sequenced exon 2 of TREM2 in a Tunisian cohort of 172 LOAD patients and 158 control subjects. We used the Fisher exact test to compare the distribution of allelic frequencies between the two groups. Results: We identified 4 previously reported nonsynonymous variants (p.Asp39Glu, p.Arg62His, p.Thr96Lys, and p.Val126Gly) and 1 novel synonymous variant (p.Gln109Gln), none of which was significantly associated with the risk of Alzheimer’s disease. Moreover, the rare TREM2 variant (p.Arg47His), which was considered to be a risk factor for Alzheimer’s disease in European descent populations, was not detected in our cohort. Conclusion: These findings do not support a major role for TREM2 in the pathogenesis of LOAD in the Tunisian population.

Download Full-text

Rare Variants in PLD3 Increase Risk for Alzheimer’s Disease in Han Chinese

Journal of Alzheimer s Disease ◽

10.3233/jad-180205 ◽

2018 ◽

Vol 64 (1) ◽

pp. 55-59 ◽

Cited By ~ 6

Author(s):

Meng-Shan Tan ◽

Jun-Xia Zhu ◽

Xi-Peng Cao ◽

Jin-Tai Yu ◽

Lan Tan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Han Chinese ◽

Increase Risk

Download Full-text

Network propagation of rare variants in Alzheimer’s disease reveals tissue-specific hub genes and communities

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008517 ◽

2021 ◽

Vol 17 (1) ◽

pp. e1008517

Author(s):

Marzia Antonella Scelsi ◽

Valerio Napolioni ◽

Michael D. Greicius ◽

Andre Altmann ◽

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Integrative Approach ◽

Specific Gene ◽

Tissue Specific ◽

Association Testing ◽

Wide Range ◽

Network Propagation

State-of-the-art rare variant association testing methods aggregate the contribution of rare variants in biologically relevant genomic regions to boost statistical power. However, testing single genes separately does not consider the complex interaction landscape of genes, nor the downstream effects of non-synonymous variants on protein structure and function. Here we present the NETwork Propagation-based Assessment of Genetic Events (NETPAGE), an integrative approach aimed at investigating the biological pathways through which rare variation results in complex disease phenotypes. We applied NETPAGE to sporadic, late-onset Alzheimer’s disease (AD), using whole-genome sequencing from the AD Neuroimaging Initiative (ADNI) cohort, as well as whole-exome sequencing from the AD Sequencing Project (ADSP). NETPAGE is based on network propagation, a framework that models information flow on a graph and simulates the percolation of genetic variation through tissue-specific gene interaction networks. The result of network propagation is a set of smoothed gene scores that can be tested for association with disease status through sparse regression. The application of NETPAGE to AD enabled the identification of a set of connected genes whose smoothed variation profile was robustly associated to case-control status, based on gene interactions in the hippocampus. Additionally, smoothed scores significantly correlated with risk of conversion to AD in Mild Cognitive Impairment (MCI) subjects. Lastly, we investigated tissue-specific transcriptional dysregulation of the core genes in two independent RNA-seq datasets, as well as significant enrichments in terms of gene sets with known connections to AD. We present a framework that enables enhanced genetic association testing for a wide range of traits, diseases, and sample sizes.

Download Full-text

Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

10.1101/294629 ◽

2018 ◽

Cited By ~ 9

Author(s):

BW Kunkle ◽

B Grenier-Boley ◽

R Sims ◽

JC Bis ◽

AC Naj ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

Association Studies ◽

Meta Analysis ◽

The Elderly ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Load Risk

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

Download Full-text

P4-097: RARE VARIANTS IN FAMILIAL LATE-ONSET ALZHEIMER'S DISEASE IDENTIFIED FROM LARGE SCALE WHOLE GENOME SEQUENCING

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3757 ◽

2019 ◽

Vol 15 ◽

pp. P1312-P1312

Author(s):

Badri N. Vardarajan ◽

James Jaworski ◽

Gary W. Beecham ◽

Sandra Barral ◽

Dolly Reyes-Dumeyer ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Large Scale ◽

Rare Variants ◽

Late Onset ◽

Whole Genome

Download Full-text

P3-004: Novel rare variants associated with late-onset Alzheimer's disease candidate genes in Caribbean Hispanic families

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.1073 ◽

2013 ◽

Vol 9 ◽

pp. P551-P551

Author(s):

Badri Vardarajan ◽

Sandra Barral ◽

Amanda Kahn ◽

Stephanie Sheikh ◽

Nicholas Rouse ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Candidate Genes ◽

Rare Variants ◽

Late Onset ◽

Hispanic Families

Download Full-text

F2-01-04: Rare variants from high-density exome genotyping in late-onset Alzheimer's disease

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.04.128 ◽

2013 ◽

Vol 9 ◽

pp. P312-P312

Author(s):

Li-San Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Rare Variants ◽

Late Onset ◽

High Density

Download Full-text

Early-Onset Alzheimer’s Disease: What Is Missing in Research?

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-020-01090-y ◽

2021 ◽

Vol 21 (2) ◽

Author(s):

Temitope Ayodele ◽

Ekaterina Rogaeva ◽

Jiji T. Kurup ◽

Gary Beecham ◽

Christiane Reitz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Onset ◽

Molecular Mechanisms ◽

Rare Variants ◽

Late Onset ◽

Aggressive Disease ◽

Clinical Biomarker ◽

Early Onset Alzheimer’S Disease ◽

Made In

Abstract Purpose of Review Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward. Recent Findings EOAD cases make up 5–10% of AD cases but only 10–15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. Summary While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.

Download Full-text