| Title |
A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
|
|---|---|
| Published in |
Acta Neuropathologica, March 2016
|
| DOI | 10.1007/s00401-016-1566-9 |
| Pubmed ID | |
| Authors |
Jan Verheijen, Tobi Van den Bossche, Julie van der Zee, Sebastiaan Engelborghs, Raquel Sanchez-Valle, Albert Lladó, Caroline Graff, Håkan Thonberg, Pau Pastor, Sara Ortega-Cubero, Maria A. Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alberto Lleó, Juan Fortea, Alexandre de Mendonça, Madalena Martins, Oriol Grau-Rivera, Ellen Gelpi, Karolien Bettens, Ligia Mateiu, Lubina Dillen, Patrick Cras, Peter P. De Deyn, Christine Van Broeckhoven, Kristel Sleegers |
| Abstract |
The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD. |
X Demographics
The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Belgium | 1 | 50% |
| United States | 1 | 50% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 157 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | <1% |
| Unknown | 156 | 99% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Researcher | 26 | 17% |
| Student > Ph. D. Student | 25 | 16% |
| Student > Bachelor | 16 | 10% |
| Student > Master | 11 | 7% |
| Student > Doctoral Student | 9 | 6% |
| Other | 28 | 18% |
| Unknown | 42 | 27% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 28 | 18% |
| Agricultural and Biological Sciences | 20 | 13% |
| Medicine and Dentistry | 17 | 11% |
| Neuroscience | 17 | 11% |
| Psychology | 8 | 5% |
| Other | 19 | 12% |
| Unknown | 48 | 31% |
Attention Score in Context
This research output has an Altmetric Attention Score of 14. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 20 July 2023.
All research outputs
#2,315,912
of 24,093,053 outputs
Outputs from Acta Neuropathologica
#556
of 2,455 outputs
Outputs of similar age
#38,050
of 305,025 outputs
Outputs of similar age from Acta Neuropathologica
#12
of 31 outputs
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