A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
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 geneti...
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Veröffentlicht in: | Acta neuropathologica 2016-08, Vol.132 (2), p.213-224 |
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Zusammenfassung: | 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. |
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ISSN: | 0001-6322 1432-0533 1432-0533 |
DOI: | 10.1007/s00401-016-1566-9 |