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O3‐13‐06: Targeted re‐sequencing of sorl1 in early‐onset Alzheimer's dementia: The european early onset dementia consortium
Author(s) -
Sleegers Kristel,
Verheijen Jan,
Zee Julie,
Bettens Karolien,
Engelborghs Sebastiaan,
Vandenbulcke Mathieu,
Sanchez-Valle Raquel,
Benussi Luisa,
Mendonça Alexandre,
Pastor Pau,
Graff Caroline,
Borroni Barbara,
Vandenberghe Rik,
Deyn Peter P.,
Broeckhoven Christine
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.07.484
Subject(s) - missense mutation , genetics , dementia , biology , frameshift mutation , alzheimer's disease , medicine , mutation , gene , disease
Background:To identify rare mutations by targeted sequencing in eight genes initially detected in genome-wide association studies (GWASs) of late onset Alzheimer’s disease (LOAD). Methods: We conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A and PICALMin three independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 NIA-LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). The variants were called using the BWA-GATK pipeline. Rare coding mutations found in at least two datasets were genotyped in independent controls similar in age and sex distributions and ancestry to the cases in all datasets to estimate population-based frequencies. Results:We detected a statistically significant 3.71-fold enrichment of the non-synonymous mutations in both cohorts of Caucasian LOAD cases compared with controls (p1⁄40.001) but the mutation rate of non-coding mutations was same in cases and controls. In total, we detected 88 rare damaging mutations, 12 of which were found in at least two datasets: four mutations in ABCA7, two each in CD2AP and PICALM, and one each in BIN1, EPHA1, CLU and MS4A6A. Three of these mutations were observed in all datasets: rs138047593 (BIN1 p.K358R), rs202178565 (EPHA1 p.P460L), and rs138650483 (MS4A6A p.V218M).. The variant in EPHA1 segregated completely in an extended Caribbean Hispanic family and was observed in only one of 300 controls of similar ancestry. Additionally, p.K358R in BIN1segregated in two of the six families where the mutations were discovered. Conclusions: Targeted sequencing of well-confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD with the greatest burden observed in ABCA7 and BIN1. The rarity of these mutations does not fully explain all the associations observed in GWAS, but do represent independent contributions to LOAD pathogenesis. Identifying coding sequence variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies.