Browsing by Author "Shade, Lincoln M. P."

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    Genome-wide association study of brain arteriolosclerosis
    (Sage, 2022) Shade, Lincoln M. P.; Katsumata, Yuriko; Hohman, Timothy J.; Nho, Kwangsik; Saykin, Andrew J.; Mukherjee, Shubhabrata; Boehme, Kevin L.; Kauwe, John S. K.; Farrer, Lindsay A.; Schellenberg, Gerard D.; Haines, Jonathan L.; Mayeux, Richard P.; Schneider, Julie A.; Nelson, Peter T.; Fardo, David W.; Radiology and Imaging Sciences, School of Medicine
    Brain arteriolosclerosis (B-ASC) is characterized by pathologically altered brain parenchymal arterioles. B-ASC is associated with cognitive impairment and increased likelihood of clinical dementia. To date, no study has been conducted on genome-wide genetic risk of autopsy-proven B-ASC. We performed a genome-wide association study (GWAS) of the B-ASC phenotype using multiple independent aged neuropathologic cohorts. Included in the study were participants with B-ASC autopsy and genotype data available from the NACC, ROSMAP, ADNI, and ACT data sets. Initial Stage 1 GWAS (n = 3382) and Stage 2 mega-analysis (n = 4569) were performed using data from the two largest cohorts (NACC and ROSMAP). Replication of top variants and additional Stage 3 mega-analysis were performed incorporating two smaller cohorts (ADNI and ACT). Lead variants in the top two loci in the Stage 2 mega-analysis (rs7902929, p =  1.8×10−7 ; rs2603462, p =  4×10−7 ) were significant in the ADNI cohort (rs7902929, p =  0.012 ; rs2603462, p = 0.012 ). The rs2603462 lead variant colocalized with ELOVL4 expression in the cerebellum (posterior probability = 90.1%). Suggestive associations were also found near SORCS1 and SORCS3. We thus identified putative loci associated with B-ASC risk, but additional replication is needed.
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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.