GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

Authors

• Lincoln M.P. Shade, University of KentuckyFollow
• Yuriko Katsumata, University of KentuckyFollow
• Erin L. Abner, University of KentuckyFollow
• Khine Zin Aung, University of Kentucky
• Steven A. Claas, University of KentuckyFollow
• Qi Qiao, University of Kentucky
• Bernardo Aguzzoli Heberle, University of KentuckyFollow
• J. Anthony Brandon, University of Kentucky
• Madeline L. Page, University of Kentucky
• Timothy J. Hohman, Vanderbilt University
• Shubhabrata Mukherjee, University of Washington
• Richard P. Mayeux, Columbia University
• Lindsay A. Farrer, Boston University
• Gerard D. Schellenberg, Boston University
• Jonathan L. Haines, University of Pennsylvania
• Walter A. Kukull, University of Washington
• Kwangsik Nho, Indiana University Bloomington
• Andrew J. Saykin, Indiana University Bloomington
• David A. Bennett, Indiana University Bloomington
• Julie A. Schneider, Rush Medical College
• Julie A. Schneider, Indiana University Bloomington
• Lindsay A. Farrer, Columbia University
• Richard P. Mayeux, University of Washington
• Subhabrata Mukherjee, Vanderbilt University
• Andrew J. Saykin, Indiana University Bloomington
• Walter A. Kukull, Case Western Reserve University

Abstract

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.

Document Type

Article

Publication Date

1-1-2024

Notes/Citation Information

Publisher Copyright: © The Author(s) 2024.

Digital Object Identifier (DOI)

10.1038/s41588-024-01939-9

Archival?

Archival

Repository Citation

Shade, Lincoln M.P.; Katsumata, Yuriko; Abner, Erin L.; Aung, Khine Zin; Claas, Steven A.; Qiao, Qi; Heberle, Bernardo Aguzzoli; 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.; Schneider, Julie A.; Farrer, Lindsay A.; Mayeux, Richard P.; Mukherjee, Subhabrata; Saykin, Andrew J.; and Kukull, Walter A., "GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia" (2024). Biostatistics Faculty Publications. 179.
https://uknowledge.uky.edu/biostatistics_facpub/179