Browsing by Author "Page, Madeline L."

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    GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia
    (Springer Nature, 2024) Shade, Lincoln M. P.; Katsumata, Yuriko; Abner, Erin L.; Aung, Khine Zin; Claas, Steven A.; Qiao, Qi; Aguzzoli Heberle, Bernardo; Brandon, J. Anthony; Page, Madeline L.; Hohman, Timothy J.; Mukherjee, Shubhabrata; Mayeux, Richard P.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Kukull, Walter A.; Nho, Kwangsik; Saykin, Andrew J.; Bennett, David A.; Schneider, Julie A.; National Alzheimer’s Coordinating Center; Ebbert, Mark T. W.; Nelson, Peter T.; Fardo, David W.; Radiology and Imaging Sciences, School of Medicine
    Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.
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    The Polygenic Risk Score Knowledge Base offers a centralized online repository for calculating and contextualizing polygenic risk scores
    (Springer Nature, 2022-09-02) Page, Madeline L.; Vance, Elizabeth L.; Cloward, Matthew E.; Ringger, Ed; Dayton, Louisa; Ebbert, Mark T. W.; Alzheimer’s Disease Neuroimaging Initiative; Miller, Justin B.; Kauwe, John S. K.; Radiology and Imaging Sciences, School of Medicine
    The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu ) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research.