Coding mutations in SORL1 and Alzheimer disease

Abstract

Importance Common single nucleotide polymorphisms in the SORL1 gene have been associated with late onset Alzheimer’s disease (LOAD) but causal variants have not been fully characterized nor has the mechanism been established. Objective To identify functional SORL1 mutations in patients with LOAD. Design and Participants This was a family- and cohort-based genetic association study. Caribbean Hispanics with familial and sporadic LOAD and similarly aged controls recruited from the United States and the Dominican Republic, and patients with sporadic disease of Northern European origin recruited from Canada. Main Outcome Measure(s) Prioritized coding variants in SORL1 detected by targeted re-sequencing and validated by genotyping in additional family members and unrelated healthy controls. Variants transfected into human embryonic kidney 293 (HEK) cell lines were tested for Aβ40 and Aβ42 secretion and the amount of the amyloid precursor protein (APP) secreted at the cell surface was determined. Results 17 coding exonic variants were significantly associated with disease. Two rare variants (rs117260922-E270K and rs143571823-T947M) with MAF<1% and one common variant (rs2298813-A528T) with MAF=14.9% segregated within families and were deemed deleterious to the coding protein. Transfected cell lines showed increased Aβ40 and Aβ42 secretion for the rare variants (E270K and T947M) and increased Aβ42 secretion for the common variant (A528T). All mutants increased the amount of APP at the cell surface, though in slightly different ways, thereby failing to direct full-length APP into the retromer-recycling endosome pathway. Conclusions and Relevance Common and rare variants in SORL1 elevate the risk of LOAD by directly affecting APP processing which, in turn can result in increased Aβ40 and Aβ42 secretion.

Molecular genetics of early‐onset Alzheimer's disease revisited

“…More, the investigation of an EOAD patient-control cohort confirmed the role of rare nonsynonymous coding variants in SORL1 as risk factor for EOAD (Table 2), with the association signal driven by familial patients [77]. Also, both common and rare, noncoding and coding variants in SORL1 have been associated with increased risk of LOAD [113][114][115]. Three SORL1 coding mutations (p.E270K and p.T947M, p.A528T) identified in a family-based and cohort-based association study on LOAD have been shown to increase Ab40 and/or Ab42 secretion when expressed in vitro [115].…”

“…Also, both common and rare, noncoding and coding variants in SORL1 have been associated with increased risk of LOAD [113][114][115]. Three SORL1 coding mutations (p.E270K and p.T947M, p.A528T) identified in a family-based and cohort-based association study on LOAD have been shown to increase Ab40 and/or Ab42 secretion when expressed in vitro [115]. These studies reinforced the role of rare variants in SORL1 in both EOAD and LOAD risk.…”

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

“…It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

From Common to Rare Variants: The Genetic Component of Alzheimer Disease

“…After focusing on cases with a positive family history ( n = 205), the OR increased to 8.86 (95% CI = 3.35-27.31), and the p value reached exome-wide significance ( p = 3.82 × 10 -7 ). The association of SORL1 rare variants was replicated in a Belgian case-control study based on targeted sequencing of 1,255 EOAD patients and 1,938 controls of European ancestry (SKAT-O p value = 0.0001) [79] , and another study investigated SORL1 rare variants in LOAD families providing some more functional data [80] .…”