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- W2980543452 abstract "The 17q21.31 MAPT locus contains an inversion polymorphism defined by two common haplotype clades (H1 and H2). The H1 clade increases risk for several sporadic neurodegenerative disorders characterized by brain region-specific neuronal loss, including APOE-ε4-negative Alzheimer's disease (AD). However, the mechanisms driving H1-associated pathogenesis and this considerable phenotypic pleiotropy remain unclear. Compromised genome integrity apparently plays a role in neurodegenerative disease. However, somatic mosaicism in the AD brain is largely unexplored. Hence we hypothesized that H1 promotes brain somatic mosaicism in a region-specific manner. We constructed a GATK MuTect2 pipeline that calls somatic single nucleotide variants (sSNVs) in unpaired whole genome sequencing (WGS) data, applies quality control filters, calculates subject-level autosome-wide somatic variant burden (sSNV count normalized by the sum of WGS coverage), and compares this burden across 17q21.31 diplotypes and in AD vs controls using linear regression adjusted for sex, age, APOE genotype, ancestry, AD status, H1 dosage, and brain region as appropriate. We undertook preliminary analyses of blood WGS data generated from APOE-ε4-positive National Institute on Aging-Late Onset Alzheimer's Disease subjects (n = 24). After quality control we detected sSNVs (mean allele frequency = 0.134; standard deviation = 0.040) in all subjects (mean subject-level sSNV count = 229.1; standard deviation = 144.4). Comparison across H1/H1 (n = 17), H1/H2 (n = 5), and H2/H2 (n = 2) diplotypes found that H1 dosage is associated with a trend of increased autosome-wide somatic variant burden (beta = 0.361; standard error = 0.199; p = 0.088). This burden is reduced (beta = −0.619; standard error = 0.229; p = 0.016) in AD (n = 13) vs controls (n= 11). These preliminary analyses demonstrate our pipeline identifies sSNVs and performs group-level comparisons of autosome-wide somatic variant burden. We will apply this pipeline to the Accelerating Medicines Partnership-Alzheimer's Disease brain WGS dataset, which is generated from AD and control dorsolateral prefrontal cortex, frontal pole, parahippocampal gyrus, inferior frontal gyrus, temporal cortex, and superior temporal gyrus tissue (n= 1900 subjects). This large dataset will enable us to robustly evaluate relationships between H1, AD, brain region, and somatic mosaicism." @default.
- W2980543452 created "2019-10-25" @default.
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- W2980543452 date "2019-07-01" @default.
- W2980543452 modified "2023-09-26" @default.
- W2980543452 title "P4-487: BRAIN SOMATIC MOSAICISM IN 17Q21.31 MAPT H1-ASSOCIATED ALZHEIMER'S DISEASE" @default.
- W2980543452 doi "https://doi.org/10.1016/j.jalz.2019.08.033" @default.
- W2980543452 hasPublicationYear "2019" @default.
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