03131nas a2200553   4500000000100000000000100001008004100002260001500043653001600058653002000074100001600094700001900110700001600129700001500145700001600160700001300176700001700189700001200206700001200218700001100230700001100241700001200252700001600264700001800280700001500298700001500313700002000328700001600348700002000364700001400384700001400398700001400412700001400426700001100440700001800451700001400469700001500483700002100498700001900519700001700538700001900555700001500574700001700589245009900606856005500705300000900760520179400769022001402563       2026                            d  c2026-09-3010aData mining10aGene regulation1 aJiuhong Nan1 aCarles A. Boix1 aShaohui Shi1 aXiaoxi Fan1 aJiacheng Ni1 aKai Wang1 aXiaoyu Shuai1 aKe Ding1 aPuqi Wu1 aYao An1 aNa Sun1 aLei Hou1 aKexuan Chen1 aXianpei Huang1 aChengyu Li1 aLeyla Akay1 aKate Louderback1 aHiba Nawaid1 aYongjin P. Park1 aXudong Fu1 aChong Liu1 aXiaoyu Li1 aYafei Yin1 aWei Mo1 aZhanghua Yang1 aWeirui Ma1 aXinyang Hu1 aDavid A. Bennett1 aManolis Kellis1 aLi-Huei Tsai1 aShamil Sunyaev1 aJingyun Li1 aXushen Xiong00aSingle-cell profiling and genetic regulation of alternative polyadenylation in the human brain  uhttps://www.nature.com/articles/s41588-026-02758-w  a1-133 aAlternative 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.  a1546-1718