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• W2896490853 abstract "Missing heritability in Alzheimer's disease (AD) remains a substantial challenge, despite efforts to pinpoint genetic contributors using genome-wide approaches. Rare risk variants are an understudied and potentially critical component of AD genetic architecture. In this study, we investigate the role of rare functional variants in an enriched, early-onset AD cohort. We curated an extreme phenotype discovery cohort of young, APOE ε4-negative AD cases and older, cognitively-intact controls using WES and WGS data from the AD Sequencing Project (ADSP) and the AD Neuroimaging Initiative (ADNI), respectively (Figure 1). Given the expected rarity of our variants of interest, we utilized a filtering-based step in lieu of a statistical test in order to overcome sample size limitations. Our discovery phase identified variants that present in two or more cases but not in controls, and are predicted to have high functional impact. In our validation phase, we took a stepwise approach of removing candidate variants that did not segregate with disease status in WashU and UCL datasets. We attempted further validation in six additional cohorts. We then investigated human brain, mouse brain, and mouse microglial expression levels of our top hit in published datasets. Overview of filtering steps taken in variant discovery and validation. Washington University in St. Louis (WashU), University College London (UCL), University of California, Los Angeles (UCLA), Alzheimer's Disease Genetic Consortium (ADGC), Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE), Amsterdam Dementia Cohort (ADC). The discovery phase yielded thirteen putative risk variants, which were scrutinized in the validation phase (Figure 1). A single variant in GEM Interacting Protein (GMIP), rs138995642-A, segregated with disease status in the WashU and UCL cohorts. The variant is rare (ExAC frequency = 2.99×10−5) and encodes a stop codon. It is significant in a Fisher's Exact Test when comparing the 8 post-discovery cases against 2 ExAC controls (Odds Ratio (OR) = 6.3, p=0.02) and suggestive using our 2 combined cohort controls (OR = 3.5, p=0.08) (Table 1). GMIP expression was significantly correlated with TREM2 expression in post-mortem brain (Figure 2). Its expression was also correlated with increased AD pathology in a mouse model of AD (Mouseac) and in mouse microglial cells exposed to beta-amyloid (Figure 3). GMIP is highly correlated with TREM2 in two independent data sets. A) GMIP and TREM2 expression in post mortem temporal cortex tissue from 162 AD cases and healthy controls in the MAYO data set (combined P = 2.2 × 10−16). B) GMIP and TREM2 expression in post-mortem dorsolateral prefrontal cortex tissue from 314 AD cases and healthy controls in the Religious Orders Study and Memory and Aging Project (ROSMAP) data set (combined P = 8.4 × 10−14). GMIP expression and pathology data from the Mouse Dementia Network (Mouseac, UCL). GMIP is highly expressed in hippocampus and cortex of homozygous TASTPM mice (transgenic for mutations on APP and PSEN1) compared to wild-type mice. Expression levels rise with increasing amyloid plaque pathology in hippocampus and cortex, but not in cerebellum (control region). The GMIP variant, rs138995642-A, is enriched in early-onset AD cases (Table 2). Gene expression data suggest GMIP's role in AD pathogenesis may relate to microglial function." @default.
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• W2896490853 date "2018-07-01" @default.
• W2896490853 modified "2023-10-11" @default.
• W2896490853 title "P4‐240: STOP‐GAIN VARIANT IN MICROGLIA‐EXPRESSED GENE <i>GMIP</i> IS ASSOCIATED WITH EARLY‐ONSET ALZHEIMER'S DISEASE" @default.
• W2896490853 doi "https://doi.org/10.1016/j.jalz.2018.07.061" @default.
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