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O1‐04‐05: NOVEL CODING VARIANTS IN TREM2 INCREASE RISK FOR ALZHEIMER'S DISEASE
Author(s) -
Cruchaga Carlos,
Jin Sheng Chih,
Benitez Bruno A.,
Karch Celeste,
Goate Alison
Publication year - 2014
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.2014.04.078
Subject(s) - trem2 , concordance , exome sequencing , exome , biology , genotype , genetics , dementia , disease , gene , medicine , mutation , receptor , myeloid cells
meta-analysis of existing genome-wide association studies on AD performed by the International Genomics of Alzheimer’s Project (IGAP), an intronic variant in SQSTM1 (rs72807343) showed sub-genome wide association with AD. We hypothesized that SQSTM1 variants could act as risk factors for AD. Methods: We systematically screened t he coding SQSTM1 region in a Belgian cohort of 435 early onset-onset AD patients and 872 control individuals.To test association between rare SQSTM1 variants (MAF<0.01) and early onset AD, we performed a rare variant burden analysis. Results: The analysis revealed 30 coding variants of which 12 were non-synonymous: 2 in AD and 9 in controls only. Significant allelic association with AD was observed for both common synonymous variants p.D2921⁄4 (OR1⁄40.82 [95%CI 0.68-0.99]; allelic p-value 0.035) and p.R3121⁄4 (OR1⁄40.81 [95%CI 0.68-0.98]; allelic p-value 0.03). We identified 2 rare variants in the ubiquitin-associated (UBA) domain of the p62 protein, which were reported in patients with PDB. Further research of these pathogenic variants in context of AD is needed. R are variant meta-analysis did not show association with AD. Conclusions: To extend our findings, we currently are screening t he coding SQSTM1 region in a large AD cohort ascertained within the European Early-Onset Dementia (EOD) consortium and originating from Italia, Spain, Sweden, Germany and Portugal. Sequencing is performed on a MiSeq-platform (Illumina) after MASTRassay target enrichment.