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[P2–116]: TRANSCRIPTOME ANALYSIS IN BLOOD AND BRAIN IDENTIFIES GENE EXPRESSION REGULATION AND CORRESPONDING QUANTITATIVE TRAIT LOCI IN ALZHEIMER's DISEASE
Author(s) -
Verheijen Jan,
Mateiu Ligia,
De Roeck Arne,
Küçükali Fahri,
Van Dongen Jasper,
Engelborghs Sebastiaan,
Vandenbulcke Mathieu,
Vandenberghe Rik,
De Deyn Peter Paul,
Van Broeckhoven Christine,
Sleegers Kristel
Publication year - 2017
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.2017.06.766
Subject(s) - biology , transcriptome , genetics , expression quantitative trait loci , gene , gene expression , quantitative trait locus , single nucleotide polymorphism , genotype
Background: TDP-43 (transactive response DNA-binding protein 43kDa) proteinopathy is closely associated with Alzheimer’s disease (AD), and affects clinical outcome in AD. TMEM106B rs1990622is a risk allele for TDP-43 proteinopathy, and its implications in clinical presentations of AD remains to be elucidated. Methods: Our subjects are from Religious Orders Study and the Rush Memory and Aging Project (ROS-MAP), two communitybased longitudinal cohort studies of older adults. Our analyses included 841 subjects with genotyping, cognitive, and pathology data (beta-amyloid, paired helical filament tau, and TDP-43 stage). Cognitive decline was defined as the slope of change in composite cognitive z-score in a general linear mixed model, controlling for age at enrollment, sex, and education. The imputed dosage of TMEM106B rs1990622 was tested for its association with cognitive decline after adjusting for AD pathology. Then, TDP-43 was included in the model, and a subsequent mediation analysis (quasi-Bayesian Monte Carlo method with 10,000 simulations) was done to evaluate whether the TMEM106Bvariant’s effect was mediated by TDP-43 proteinopathy. Of note, all analyses were adjusted for study cohort (ROS vs MAP), genotyping platform, and first three principal components from the genotype covariance matrix. Results:TMEM106B rs1990622was associated with more rapid cognitive decline when controlled for the AD pathology (EE1⁄4-0.0098, 95% confidence interval (CI) -0.018 to -0.0016, p1⁄40.020). When TDP-43 stage was also controlled, the association of rs1990622 with cognitive decline loses statistical significance (p1⁄40.078). A mediation analysis shows that about 15% of the association between rs1990622 and more rapid cognitive decline is mediated by more advanced TDP-43 stages (average causal mediation effect p<0.0001). Conclusions: TMEM106B rs1990622, a known TDP-43 proteinopathy risk variant, is associated with more rapid cognitive decline in people with similar degree of AD pathology, and this association is mediated by more advanced TDP-43 stages. Nonetheless, the association of rs1990622 with more rapid cognitive decline in AD is only partially explained by the link between rs1990622 and more advanced TDP-43 stages.