Proteome-Wide Association Analysis of Alzheimer's Disease Using Cerebrospinal Fluid Protein Data Open Access

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with high heritability (60-80%). While genome-wide association studies (GWAS) have identified over 75 genetic risk loci, determining causal genes and biological mechanisms remains challenging. This study addresses these limitations by adapting OTTERS, a framework originally designed for transcriptome-wide association studies (TWAS), to perform proteome-wide association studies (PWAS) using cerebrospinal fluid (CSF) protein data.

Unlike traditional PWAS that rely on plasma samples or require individual-level reference data, our approach leverages summary-level CSF proteomics, which more directly reflects brain pathology in neurological disorders. We analyzed 741 CSF proteins using four different polygenic risk score (PRS) methods to account for diverse genetic architectures and combined results through an omnibus test.

Our analysis identified 13 proteins significantly associated with Alzheimer's disease after Bonferroni correction (p < 6.75E-5). Clusterin (CLU) showed the strongest association (p = 3.30E-35), followed by Interleukin-34 (IL34) and Fructose-bisphosphate aldolase A (ALDOA). While ten proteins confirmed previous AD associations, three novel proteins (ALDOA, RNF43, and SIGLEC9) represent potential new biomarkers or therapeutic targets.

This study demonstrates that CSF proteogenomics offers valuable insights into AD pathogenesis and that summary-level data approaches can maintain statistical power while increasing data accessibility. Our findings bridge the gap between genetic associations and protein-level changes, providing a framework for understanding the biological mechanisms underlying Alzheimer's disease.

Table of Contents

CHAPTER 1: INTRODUCTION 1

CHAPTER 2: METHODS 4

Data Sources 4

Protein Selection and Processing 4

Data Extraction and Preparation 5

OTTERS Two-Stage Analysis 5

Omnibus Testing with ACAT-O 6

CHAPTER 3: RESULTS 8

CHAPTER 4: DISCUSION 15

REFERENCES 16

About this Master's Thesis

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School	Rollins School of Public Health
Department	Biostatistics
Subfield / Discipline	Biostatistics - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Keyword	OTTERS PWAS Cerebrospinal Fluid Alzheimer's Disease
Committee Chair / Thesis Advisor	Epstein, Michael P., Emory University
Committee Members	Yang, Jingjing, Emory University

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