Allele specific expression in Alzheimer's disease.

INTRODUCTION

Allele-specific expression (ASE), preferential expression of one allele at a heterozygous locus, is implicated in various brain diseases but remains largely uncharacterized in Alzheimer's disease (AD).

METHODS

We performed a genome-wide characterization of ASE variants across seven brain regions of 2,231 AD and Control patients from Mount Sinai Brain Bank (MSBB) and Religious Orders Study/Memory and Aging Project (ROSMAP) cohorts and investigated cell-type-specific activity via single-cell analysis.

RESULTS

We identified 56,136 unique ASE variants that were enriched in imprinted chromosomal regions, e.g., chr6, chr14q32, and chr15q11. ASE variants were also found in exons of known AD-associated genes, including apolipoprotein E (APOE), CLU, CTSB, and HLA-DRB1. Forty variants exhibited AD-associated ASE, and the affected genes, including SLC12A5, SYT13, and TOMM7, were predominantly downregulated in multiple cell types, including astrocytes, excitatory neurons, and oligodendrocytes.

DISCUSSION: We provided a detailed landscape of ASE in AD, uncovering novel functional variants and highlighting their potential cell-type-specific contributions to disease pathogenesis.