Evidence map›Paper›PMID 42816601›Full record

ArticleNature genetics2026

Single-cell profiling and genetic regulation of alternative polyadenylation in the human brain.

Jiuhong Nan, Carles A Boix, Shaohui Shi, Xiaoxi Fan, Jiacheng Ni, Kai Wang, Xiaoyu Shuai, Ke Ding, Puqi Wu, Yao An and 23 more

Abstract read
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In one paragraph

Article in Nature genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

33 authors.

Jiuhong Nan *The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Carles A Boix *Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Carles_Boix@hms.harvard.edu.ORCID http://orcid.org/0000-0001-9212-856X
Shaohui Shi *The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Xiaoxi FanThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0009-0009-9495-457X
Jiacheng NiZhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Kai WangDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Xiaoyu ShuaiSir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Ke DingThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Puqi WuDepartment of Psychiatry and Department of Immunology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
Yao AnDepartment of Biochemistry and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Na SunThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Lei HouDepartment of Medicine, Biomedical Genetics Section, Boston University, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0540-2706
Kexuan ChenThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Xianpei HuangThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Chengyu LiThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Leyla AkayThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kate LouderbackThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Hiba NawaidPicower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Yongjin P ParkDepartment of Pathology and Laboratory Medicine and Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.ORCID http://orcid.org/0000-0001-8915-2876
Xudong FuThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0001-7024-0200
Chong LiuDepartment of Neurosurgery of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0001-6578-5919
Xiaoyu LiDepartment of Biochemistry and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0009-0006-9840-6704
Yafei YinDepartment of Biochemistry and Department of Gastroenterology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0002-0171-844X
Wei MoDepartment of Psychiatry and Department of Immunology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China.ORCID http://orcid.org/0000-0002-8165-4473
Zhanghua YangDepartment of Psychiatry and Department of Immunology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Liangzhu Laboratory, Zhejiang University, Hangzhou, China.ORCID http://orcid.org/0000-0001-8713-1879
Weirui MaZhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Xinyang HuThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.ORCID http://orcid.org/0000-0002-6699-8470
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Manolis KellisThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-7113-9630
Li-Huei TsaiThe Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1262-0592
Shamil SunyaevDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Jingyun LiSir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Xushen XiongThe Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China. xiongxs@zju.edu.cn.ORCID http://orcid.org/0000-0001-7090-7503

Funding

Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2024YFF1207600, 2023YFA1800700National Natural Science Foundation of China (National Science Foundation of China) 32422017, 92353301, 32370609Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation) LR25C060002U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) P30AG10161, P30AG72975, R01AG15819, R01AG17917, U01AG46152, U01AG61356
6 · The paper itself

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.

Identifiers

PMID42816601

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