SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

Charbonnier, Camille; Quenez, Olivier; Bellenguez, Céline; Grenier‐Boley, Benjamin; Rousseau, Stéphane; Richard, A.; Rovelet‐Lecrux, Anne; Guennec, Kilan Le; Bacq, Delphine; Garnier, JG; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, J-F; Amouyel, Philippe; Münter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frébourg, Thierry; Redon, Richard; Letenneur, Luc; Jf, Dartigues; Génin, Emmanuelle; Lambert, Jean‐Charles; Hannequin, Didier; Campion, Dominique; Wallon, David; Martinaud, Olivier; Nicolas, Gaël; Godefroy, Olivier; Etcharry-Bouyx, Frédérique; Chauviré, Valérie; Chamard, Ludivine; Berger, Eric G.; Magnin, Éloi; Dartigues, Jean‐François; Auriacombe, Sophie; Sayette, Vincent de La; Viader, Fausto; Castan, Dominique; Dionet, Elsa; Sellal, François; Rouaud, Olivier; Thauvin, Christel; Moreaud, Olivier; Sauvée, Mathilde; Rollin‐Sillaire, Adeline; Bombois, Stéphanie; Mackowiak, Marie-Anne; Deramecourt, Vincent; Pasquier, Florence; Formaglio, Maïté; Mollion, Hélène; Roullet-Solignac, Isabelle; Vighetto, Alain; Croisile, Bernard; Didic, Mira; Félician, Olivier; Koric, Lejla; Ceccaldi, Mathieu; Gabelle, Audrey; Marelli, Cécilia; Touchon, Jacques; Labauge, Pierre; Jonveaux, Thérèse Rivasseau; Vercelletto, Martine; Boutoleau‐Bretonnière, Claire; Castelnovo, Giovanni; Renaud, D.L.; Robert, Philippe; Paquet, Claire; Dumurgier, Julien; Hugon, Jacques; Michon, Agnès; Ber, Isabelle Le; Dubois, Bruno; Duyckaerts, Charles; Boisgueheneuc, Foucauld De; Belliard, Serge; Bakchine, Serge; Barrellon, Marie-Odile; Laurent, Bernard; Blanc‬, ‪Frederic; Tranchant, Christine; Pariente, Jérémie; Puel, Michèle; Hommet, Caroline; Mondon, Karl

doi:10.1038/mp.2015.121

Cited by 102 publications

(89 citation statements)

References 24 publications

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“…This specific mutation was shown to reduce the capability of the VPS10P domain to bind Ab, resulting in accumulation of the peptide and lower turnover [112]. More, the investigation of an EOAD patient-control cohort confirmed the role of rare nonsynonymous coding variants in SORL1 as risk factor for EOAD (Table 2), with the association signal driven by familial patients [77]. Also, both common and rare, noncoding and coding variants in SORL1 have been associated with increased risk of LOAD [113][114][115].…”

Section: The Missing Genetics Of Eoadmentioning

confidence: 55%

“…It also suggested that the APOE ε4-allele may modify the expression of other genetic factors contributing to disease. However, web 4C=FPO web 4C=FPO Nonsynonymous rare variants Increased risk-signal driven by positive family history [77] Abbreviations: EOAD, early-onset Alzheimer disease; SNVs, single nucleotide variants; AAO, age-at-onset. 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 familial aggregation of EOAD cannot fully be explained by APOE as both carriers and noncarriers of a ε4-allele have an increased risk in the presence of a positive family history.…”

Section: Apoe In Eoadmentioning

confidence: 99%

See 1 more Smart Citation

Molecular genetics of early‐onset Alzheimer's disease revisited

Cacace

Sleegers

Broeckhoven

2016

Alzheimer's & Dementia

436

365

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As the discovery of the Alzheimer's disease (AD) genes, APP, PSEN1, and PSEN2, in families with autosomal dominant early-onset AD (EOAD), gene discovery in familial EOAD came more or less to a standstill. Only 5% of EOAD patients are carrying a pathogenic mutation in one of the AD genes or a apolipoprotein E (APOE) risk allele ε4, most of EOAD patients remain unexplained. Here, we aimed at summarizing the current knowledge of EOAD genetics and its role in ongoing approaches to understand the biology of AD and disease symptomatology as well as developing new therapeutics. Next, we explored the possible molecular mechanisms that might underlie the missing genetic etiology of EOAD and discussed how the use of massive parallel sequencing technologies triggered novel gene discoveries. To conclude, we commented on the relevance of reinvestigating EOAD patients as a means to explore potential new avenues for translational research and therapeutic discoveries.

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Section: The Missing Genetics Of Eoadmentioning

confidence: 55%

Section: Apoe In Eoadmentioning

confidence: 99%

Molecular genetics of early‐onset Alzheimer's disease revisited

Cacace

Sleegers

Broeckhoven

2016

Alzheimer's & Dementia

436

365

View full text Add to dashboard Cite

show abstract

“…As illustrated by SORL1 and ABCA7 , common variants identified by GWAS can target genes where rare coding variants are also associated with AD risk [23,78,82,85] . The CLU gene is another GWAS hit for which an enrichment of rare variants clustered in exons 5-8 has been reported in AD patients.…”

Section: Rare Variant Association and Gwas Hitsmentioning

confidence: 99%

“…However, this approach which succeeded with ABCA7 , missed SORL1 , probably due to the study design. Indeed, SORL1 loss-offunction variants are hardly ever found in non-AD subjects [78,86] , which have been used for the variants' discovery [85] . No other significant signal was reported for other GWAS hits in this study [85] .…”

Section: Rare Variant Association and Gwas Hitsmentioning

confidence: 99%

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

Nicolas

Charbonnier²,

Campion³

2016

Hum Hered

Self Cite

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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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Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport

et al. 2017

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PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. OBJECTIVE To search for rare variants contributing to the risk for EOAD. DESIGN, SETTING, AND PARTICIPANTS In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. MAIN OUTCOMES AND MEASURES Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. RESULTS Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10 −6 ; Bonferroni-corrected Pvalue [BP] = 1.3 × 10 −3) and LOAD (P = 6.22 × 10 −6 ; BP = 4.1 × 10 −3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10 −4 ;BP = 5.0 × 10 −3). A missense variant in the LOAD riskgeneRIN3showedsuggestiveevidenceofassociationwithEOADafterBonferronicorrection(OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2NHWEOADcasesshowedsuggestiveevidenceofanassociationwithEOADaswell(OR,18.63;95% CI, 1.62-213.45; P = .003; BP = 0.129). CONCLUSIONS A...

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SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

Cited by 102 publications

References 24 publications

Molecular genetics of early‐onset Alzheimer's disease revisited

Molecular genetics of early‐onset Alzheimer's disease revisited

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

Early-Onset Alzheimer Disease and Candidate Risk Genes Involved in Endolysosomal Transport

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