Abstract
Abstract
Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types and its contribution to genetic disease have remained unclear. Here we report a single-cell atlas of APA of the aged human brain across 2 million cells from 379 human postmortem brains across individuals with and without Alzheimer’s disease (AD). We show that APA provides an independent mechanistic layer for understanding gene regulatory changes in AD, as genes with APA alterations are distinct from those with expression changes but often converge to similar pathways, including microglial activation and microtubule transport in neurons. We integrate APA variation with whole-genome sequencing to identify cell-type-resolved 3′ untranslated region quantitative trait loci (3′aQTLs) for 4,288 genes. We find that 3′aQTLs preferentially colocalize with pQTLs over eQTLs. Across 17 brain traits and diseases, we identify 168 GWAS loci dependent on 3′aQTLs, of which only 17.5% are shared with eQTLs. These include
PLEKHA1
and
APOC2
for AD,
PAK6
and
AP3B2
for schizophrenia,
NDUFA13
for bipolar disorder,
MTCH2
for multiple brain traits, and
SNCA
, the top locus in Parkinson’s disease. We show that 3′ untranslated region choice alters
SNCA
mRNA localization within the cell, consistent with the observation that the
SNCA
risk locus acts in an eQTL-independent manner in neurons and oligodendrocytes. Our results provide a cell-type-specific foundation to interrogate the
cis
and
trans
regulation of APA and to understand the contribution to disease heritability of this key post-transcriptional layer.