TY - JOUR
T1 - A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
AU - Verheijen, Jan
AU - van Den Bossche, Tobi
AU - van der Zee, Julie
AU - Engelborghs, Sebastiaan
AU - Sanchez-Valle, Raquel
AU - Lladó, Albert
AU - Graff, Caroline
AU - Thonberg, Håkan
AU - Pastor, Pau
AU - Ortega-Cubero, Sara
AU - Pastor, Maria A.
AU - Benussi, Luisa
AU - Ghidoni, Roberta
AU - Binetti, Giuliano
AU - Clarimon, Jordi
AU - Lleó, Alberto
AU - Fortea, Juan
AU - de Mendonça, Alexandre
AU - Martins, Madalena
AU - Grau-Rivera, Oriol
AU - Gelpi, Ellen
AU - Bettens, Karolien
AU - Mateiu, Ligia
AU - Dillen, Lubina
AU - Cras, Patrick
AU - de Deyn, Peter P.
AU - van Broeckhoven, Christine
AU - Sleegers, Kristel
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Alzheimer
KW - Early onset
KW - Haploinsufficiency
KW - Loss-of-function
KW - Meta-analysis
KW - Rare variants
KW - SORL1
UR - http://www.scopus.com/inward/record.url?scp=84962272006&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962272006&partnerID=8YFLogxK
U2 - 10.1007/s00401-016-1566-9
DO - 10.1007/s00401-016-1566-9
M3 - Article
AN - SCOPUS:84962272006
VL - 132
SP - 213
EP - 224
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 2
ER -