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- W2980673464 abstract "We sought to find genetic associations for relative memory performance among individuals with late-onset Alzheimer's disease. APOE ε4 is a strong predictor for this phenotype. We hypothesized that genetic architecture of this phenotype outside the APOE region could vary substantially across APOE genotypes. We used structural equation models to derive co-calibrated scores for memory, visuospatial functioning, language, and executive functioning for people with Alzheimer's disease across five studies. We determined each person's cross-domain average across the four cognitive domain scores. We determined relative impairment for memory by calculating differences between memory score and their cross-domain average. These continuous relative impairment scores were our target phenotype. We ran genome-wide association studies (GWAS) of each of the four relative impairments using PLINK on the 1000G imputed data (NCBI; build 137) from participants of European descent in ACT, ADNI, ROS, MAP, and University of Pittsburgh data sets. We controlled each analysis for sex, age at diagnosis, education, and population substructure. We used METAL to meta-analyze results. We ran APOE ε4 stratified GWAS. We used those results to perform a gene-wide analyses with ±50kb mapping using VEGASv2 (genome-wide significance =2.5x10−6). We used gene-wide association results together with human protein-protein interaction (PPI) data to identify networks using dense module searching (DMS). Total sample size was n=2,419 out of which 1,200 had ≥1 APOE ε4 allele and 1,219 had 0 APOE ε4 alleles. In the whole sample, outside the APOE region, we found a suggestive association between our phenotype and variants in GRPEL2 (p= 1.2×10−4) on Chromosome 5. For people with ≥1 APOE ε4 allele, our top finding was for OR2G6 (p= 3×10−4) on Chromosome 1, and for people with 0 APOE e4 alleles, it was ERMN (p= 1.6×10−4) on Chromosome 2. We identified very different networks across APOE genotypes. People with ≥1 APOE e4 allele had a network characterized by a hub driven by APP, while that of people with 0 APOE e4 alleles was driven by UBC." @default.
- W2980673464 created "2019-10-25" @default.
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- W2980673464 date "2019-07-01" @default.
- W2980673464 modified "2023-10-18" @default.
- W2980673464 title "P4-494: GENETIC ARCHITECTURE OF RELATIVE MEMORY PERFORMANCE AMONG PEOPLE WITH ALZHEIMER'S DISEASE DIFFERS BY APOE GENOTYPE ACROSS FIVE COHORTS" @default.
- W2980673464 doi "https://doi.org/10.1016/j.jalz.2019.08.040" @default.
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