A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1566-9) contains supplementary material, which is available to authorized users.

Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease

“…In contrast to other hits from gene-wide association studies, which typically confer a small increase in AD risk, SORL1 variants have been found that confer a five-fold risk (Vardarajan et al, 2015; Verheijen et al, 2016), on par with APOE4 carriers. More importantly, recent studies suggest that rare SORL1 mutations are actually causal mutations (Pottier et al, 2012; Vardarajan et al, 2015), akin to the autosomal-dominant mutations in APP or PSEN s (Holstege et al, 2017).…”

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

“…SORL1 , was initially identified as a risk-factor in a case-control association-study [23], but has more recently been implicated in familial early-onset as well as late-onset AD [8, 16, 20, 21, 25, 26]. …”

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer’s Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

“…The variant was not detected in any other subject in the Amsterdam Dementia cohort. One study detected the variant in a 63-year-old healthy female (control group n  = 1938, MAF <0.001) [26], and the ExAC database reports only one heterozygous carrier of this variant (MAF <0.00001). The variant locus is at a highly conserved glycosylation site in the VPS10 domain of SORL1 (Fig.…”