Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

Patel, Devanshi; Mez, Jesse; Vardarajan, Badri N.; Staley, Lyndsay A.; Chung, Jaeyoon; Zhang, Xiaoling; Farrell, John; Rynkiewicz, Michael J.; Cannon-Albright, Lisa; Teerlink, Craig C.; Stevens, Jeffery; Corcoran, Christopher; Murcia, Josue D. Gonzalez; López, Oscar L.; Mayeux, Richard; Haines, Jonathan L.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.; Kauwe, John; Lunetta, Kathryn L.; Farrer, Lindsay A.

doi:10.1001/jamanetworkopen.2019.1350

Cited by 62 publications

(62 citation statements)

References 75 publications

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“…Of genes with SLPs above 3, a number have previously been implicated by sequencing studies, consisting of TREM2 , ABCA7 , SORL1 , and PSEN1 (Blue et al., ; Guerreiro et al., ; Kim, ; Patel et al., ; Raghavan et al., ). Many of the others did not seem likely to have any plausible role in AD susceptibility but there were some exceptions that we list here.…”

Section: Resultsmentioning

confidence: 99%

“…Using gene‐based analyses in the ADSP case‐control sample, TREM2 was significant at p = 1.8 × 10 −11 and APOE was significant at p = 0.0069, while ARSA , CSF1R , PSEN1 , and MAPT were less strongly implicated although were still significant at p < 0.05. In another study, 95 dementia‐associated genes were examined and it was reported that overall there was an excess of deleterious rare coding variants (Patel et al., ). Additionally, 10 cases and no controls carried rs149307620, a missense variant in NOTCH3 , and four cases and no controls carried rs104894002, a high‐impact variant in TREM2 , which in homozygous form causes Nasu–Hakola disease, which is a rare presenile dementia associated with recurrent bone fractures.…”

Section: Introductionmentioning

confidence: 99%

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Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2020

Annals of Human Genetics

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Previous studies have implicated common and rare genetic variants as risk factors for late‐onset Alzheimer's disease (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. Because 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 Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2020

Annals of Human Genetics

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“…Despite a less aggressive progression, SAD shares the major characteristics of FAD, including Aβ plaque deposition and NFT pathology, and accounts for the vast majority (>95%) of all AD cases [28]. While no SAD-causative mutations have been found, a considerable number of genetic loci that increase or decrease the risk for developing SAD have now been reported [29][30][31][32][33][34]. The first identified was the APOE locus, encoding apolipoprotein E (APOE) [35].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Modeling Alzheimer’s disease with iPSC-derived brain cells

2019

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Alzheimer's disease is a devastating neurodegenerative disorder with no cure. Countless promising therapeutics have shown efficacy in rodent Alzheimer's disease models yet failed to benefit human patients. While hope remains that earlier intervention with existing therapeutics will improve outcomes, it is becoming increasingly clear that new approaches to understand and combat the pathophysiology of Alzheimer's disease are needed. Human induced pluripotent stem cell (iPSC) technologies have changed the face of preclinical research and iPSC-derived cell types are being utilized to study an array of human conditions, including neurodegenerative disease. All major brain cell types can now be differentiated from iPSCs, while increasingly complex co-culture systems are being developed to facilitate neuroscience research. Many cellular functions perturbed in Alzheimer's disease can be recapitulated using iPSC-derived cells in vitro, and co-culture platforms are beginning to yield insights into the complex interactions that occur between brain cell types during neurodegeneration. Further, iPSC-based systems and genome editing tools will be critical in understanding the roles of the numerous new genes and mutations found to modify Alzheimer's disease risk in the past decade. While still in their relative infancy, these developing iPSC-based technologies hold considerable promise to push forward efforts to combat Alzheimer's disease and other neurodegenerative disorders.

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“…Of genes with SLPs above 3, a number have previously been implicated by sequencing studies, consisting of TREM2, ABCA7, SORL1 and PSEN1 (Blue et al, 2018;Guerreiro et al, 2013;Kim, 2018;Patel et al, 2019;Raghavan et al, 2018). PIK3R1 codes for a key component of the PI3K/Akt/GSK-3β signalling pathway and in neuronally differentiated PC12 cells activation of this pathway is neuroprotective against Aβ25-35-induced apoptosis and tau hyperphosphorylation (Cheng et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

Curtis

Bakaya²,

Sharma³

et al. 2019

Preprint

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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.

show abstract

Association of Rare Coding Mutations With Alzheimer Disease and Other Dementias Among Adults of European Ancestry

Cited by 62 publications

References 75 publications

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Weighted burden analysis of exome‐sequenced late‐onset Alzheimer's cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK‐3β and WNT signalling pathways

Modeling Alzheimer’s disease with iPSC-derived brain cells

Weighted burden analysis of exome-sequenced late onset Alzheimer’s cases and controls provides further evidence for a role for PSEN1 and suggests involvement of the PI3K/Akt/GSK-3β and WNT signalling pathways

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