Fuzzy Nature of AD Risk Gene Assignments to Brain Cell Types

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Abstract/Contents

Abstract: As AD pathophysiology remains elusive, risk genes offer valuable information lending clinical and pathophysiological insights into the disease. Assignment of cell type for the AD risk genes proves crucial for understanding underlying pathophysiology. This cell type assignment will often have to be granular, necessitating the use of marker and algorithmic cell type information transfer between datasets. We train and validate a cell type labeling neural network on a scRNA dataset and demonstrate its poor generalization to labeling an snRNA dataset. We extend this analysis to show that for the purpose of assigning cell type labels, markers and the neural network approach respectively lose information when compared to the dataset’s ground truth labels. We systematically analyze these AD risk genes by their cell type assignment, and detail cortical regional effects on cell type assignment. We show that while ANK3, CLU, APP, EPDR1, PLEKHA1, and ICA1 are neuronally dominant in their expression, only CLU, and PLEKHA1 have expression profiles that appear to vary by neuronal subtype. Lastly, we demonstrate that AD candidate drug targets (APOE, GRN) are likely functionally expressed in multiple cell types and thus pose risks, while suggesting other candidates that are functionally expressed in only one cell type.

Author	Schonfeld, Ethan
Thesis advisor	Südhof, Thomas
Thesis advisor	Fraser, Hunter
Degree granting institution	Stanford University, Department of Biology

Subject	Biology
Subject	Transcriptomics
Subject	Neural networks (Computer science)
Subject	GWAS
Subject	Cell Type Assignment
Subject	Alzheimer's disease
Genre	Text
Genre	Thesis

DOI	https://doi.org/10.25740/bt657fp5872
Location	https://purl.stanford.edu/bt657fp5872

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License: This work is licensed under a Creative Commons Attribution Non Commercial 4.0 International license (CC BY-NC).

Preferred citation: Schonfeld, E. and Südhof, T. (2022). Fuzzy Nature of AD Risk Gene Assignments to Brain Cell Types. Stanford Digital Repository. Available at https://purl.stanford.edu/bt657fp5872

Undergraduate Theses, Department of Biology, 2021-2022

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