<i>ABCA7</i>
            rare variants and Alzheimer disease risk

Guennec, Kilan Le; Nicolas, Gaël; Quenez, Olivier; Charbonnier, Camille; Wallon, David; Bellenguez, Céline; Grenier‐Boley, Benjamin; Rousseau, Stéphane; Richard, Anne-Claire; Rovelet‐Lecrux, Anne; Bacq, Delphine; Garnier, Jean-Guillaume; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, Jean‐François; Amouyel, Philippe; Münter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frébourg, Thierry; Redon, Richard; Letenneur, Luc; Dartigues, Jean‐François; Pasquier, Florence; Rollin‐Sillaire, Adeline; Génin, Emmanuelle; Lambert, Jean‐Charles; Hannequin, Didier; Campion, Dominique

doi:10.1212/wnl.0000000000002627

Cited by 63 publications

(64 citation statements)

References 28 publications

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“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

Section: Methodsmentioning

confidence: 99%

“…It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

Section: Introductionmentioning

confidence: 99%

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Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.MethodsWe analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.ResultsA variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).Conclusions and RelevanceRare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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“…Finally, a meta-analysis including ABCA7 disruptive plus missense strictly damaging variants in the Belgian sample and in WES data from 484 EOAD and 590 French controls reached exome-wide significance with an OR of 2.81 (95% CI 1.89-4.20; p = 3.6 × 10 -7 ) [87] , thus providing an independent replication of the original finding.…”

Section: The Sorl1 Genementioning

confidence: 53%

“…Increased sample sizes, meta-analyses, and novel strategies will allow new hits to be detected, although the methodological challenge remains high among this huge diversity and the extreme rarity of genetic variations. Finally, at the individual or at the family level, aggregation of rare risk factors [87] as well as the co-occurrence of rare risk factors with APOE ε 4+ genotypes have been observed [87,109] . Measuring the effect of the combination of rare variants with other rare and/or frequent variants is an even higher methodological challenge for the future years.…”

Section: Discussionmentioning

confidence: 99%

“…Looking at the ABCA7 gene, a loss-of-function variant was detected in 6 relatives with AD or mild or subjective cognitive impairment in a Belgian family [86] . However, this cosegregation should not be interpreted as a definite evidence of Mendelian inheritance in this family given that (i) ABCA7 loss-of-function variants increase AD risk only moderately and that (ii) ABCA7 loss-of-function variant carriers compose 0.6-1% of controls [86,87] , including some controls known as cognitively intact [85][86][87] .…”

Section: Segregation Of Rare Variants In Complex Disordersmentioning

confidence: 99%

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From Common to Rare Variants: The Genetic Component of Alzheimer Disease

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

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Alzheimer disease (AD) is a remarkable example of genetic heterogeneity. Extremely rare variants in the APP, PSEN1, or PSEN2 genes, or duplications of the APP gene cause autosomal dominant forms, generally with complete penetrance by the age of 65 years. Nonautosomal dominant forms are considered as a complex disorder with a high genetic component, whatever the age of onset. Although genetically heterogeneous, AD is defined by the same neuropathological criteria in all configurations. According to the amyloid cascade hypothesis, the Aβ peptide, which aggregates in AD brains, is a key player. APP, PSEN1, or PSEN2 gene mutations increase the production of more aggregation-prone forms of the Aβ peptide, triggering the pathological process. Several risk factors identified in association studies hit genes involved in Aβ production/secretion, aggregation, clearance, or toxicity. Among them, the APOE ε4 allele is a rare example of a common allele with a large effect size, the ORs ranging from 4 to 11-14 for heterozygous and homozygous carriers, respectively. In addition, genome-wide association studies have identified more than two dozen loci with a weak but significant association, the OR of the at-risk allele ranging from 1.08 to 1.30. Recently, the use of massive parallel sequencing has enabled the analysis of rare variants in a genome-wide manner. Two rare variants have been nominally associated with AD risk or protection (TREM2 p.R47H, MAF approximately 0.002, OR approximately 4 and APP p.A673T, MAF approximately 0.0005, OR approximately 0.2). Association analyses at the gene level identified rare loss-of-function and missense, predicted damaging, variants (MAF <0.01) in the SORL1 and ABCA7 genes associated with a moderate relative risk (OR approximately 5 and approximately 2.8, respectively). Although the latter analyses revealed association signals with moderately rare variants by collapsing them, the power to detect genes hit by extremely rare variants is still limited. An alternative approach is to consider the de novo paradigm, stating that de novo variants may contribute to AD genetics in sporadic patients. Here, we critically review AD genetics reports with a special focus on rare variants.

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ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease

Lyssenko

Praticò

2020

Alzheimer's & Dementia

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We propose the altered lipidostasis hypothesis of Alzheimer's disease (AD). It holds that vulnerable neurons of the entorhinal region generate a neurodegenerative lipid during normal function, adenosine triphosphate–binding cassette transporter subfamily A member 7 (ABCA7) protects from AD pathogenesis by removing it out of the cell, generation of the lipid increases with age, and the minimal amount of ABCA7 needed to dispose of the rising volumes of the lipid also increases with age. A survey of ABCA7 protein levels in the hippocampus or parietal cortex of 123 individuals with or without AD neuropathology showed that individuals with low ABCA7 developed AD neuropathology at a younger age, those with intermediate ABCA7 developed it later, and individuals who developed it very late had high ABCA7, the same as the youngest controls. ABC transporters closely similar to ABCA7 protect cells by removing toxic lipids. ABCA7 may have analogous functions. The hypothesis predicts lipidosis and membrane protein dysfunction in neurons with low ABCA7. Further work will identify the neurodegenerative lipid and determine approaches to exploit ABCA7 for therapeutic purposes.

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ABCA7 rare variants and Alzheimer disease risk

Abstract: These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.

Cited by 63 publications

References 28 publications

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

ABCA7 and the altered lipidostasis hypothesis of Alzheimer's disease

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