Evidence map›Paper›PMID 36945630›Full record

ArticlemedRxiv : the preprint server for health sciences2023

Cross-ancestry, cell-type-informed atlas of gene, isoform, and splicing regulation in the developing human brain.

Cindy Wen, Michael Margolis, Rujia Dai, Pan Zhang, Pawel F Przytycki, Daniel D Vo, Arjun Bhattacharya, Nana Matoba, Chuan Jiao, Minsoo Kim and 27 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2023. 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, 15 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors at 14 institutions in 5 countries.

Cindy WenInterdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Michael MargolisDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Rujia DaiDepartment of Psychiatry, SUNY Upstate Medical University; Syracuse, NY, 13210, USA.
Pan ZhangDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Pawel F PrzytyckiGladstone Institute of Data Science and Biotechnology; San Francisco, CA, 94158, USA.
Daniel D VoDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Arjun BhattacharyaDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Nana MatobaDepartment of Genetics, University of North Carolina at Chapel Hill; Chapel Hill, NC, 27599, USA.
Chuan JiaoDepartment of Psychiatry, SUNY Upstate Medical University; Syracuse, NY, 13210, USA.
Minsoo KimDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Ellen TsaiDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Celine HohDepartment of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Nil AygünDepartment of Genetics, University of North Carolina at Chapel Hill; Chapel Hill, NC, 27599, USA.
Rebecca L WalkerInterdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Christos ChatzinakosDepartment of Psychiatry, Harvard Medical School; Boston, MA, 02215, USA.
Declan ClarkeDepartment of Molecular Biophysics and Biochemistry, Yale University; New Haven, CT, 06520, USA.
Henry PrattProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School; Worcester, MA, 01605, USA.
PsychENCODE ConsortiumInterdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Mette A PetersCNS Data Coordination Group, Sage Bionetworks; Seattle, WA, 98109, USA.
Mark GersteinDepartment of Molecular Biophysics and Biochemistry, Yale University; New Haven, CT, 06520, USA.
Nikolaos P DaskalakisDepartment of Psychiatry, Harvard Medical School; Boston, MA, 02215, USA.
Zhiping WengProgram in Bioinformatics and Integrative Biology, University of Massachusetts Medical School; Worcester, MA, 01605, USA.
Andrew E JaffeLieber Institute for Brain Development; Baltimore, MD, 21205, USA.
Joel E KleinmanLieber Institute for Brain Development; Baltimore, MD, 21205, USA.
Thomas M HydeLieber Institute for Brain Development; Baltimore, MD, 21205, USA.
Daniel R WeinbergerLieber Institute for Brain Development; Baltimore, MD, 21205, USA.
Nicholas J BrayMRC Centre for Neuropsychiatric Genetics & Genomics, Division of Psychological Medicine & Clinical Neurosciences, Cardiff University School of Medicine; Cardiff, CF24 4HQ, UK.
Nenad SestanDepartment of Comparative Medicine, Yale University School of Medicine; New Haven, CT, 06520, USA.
Daniel H GeschwindDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Kathryn RoederDepartment of Statistics & Data Science, Carnegie Mellon University; Pittsburgh, PA, 15213, USA.
Alexander GusevDepartment of Medical Oncology, Division of Population Sciences, Dana-Farber Cancer Institute; Boston, MA, 02215, USA.
Bogdan PasaniucInterdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
Jason L SteinDepartment of Genetics, University of North Carolina at Chapel Hill; Chapel Hill, NC, 27599, USA.
Michael I LoveDepartment of Genetics, University of North Carolina at Chapel Hill; Chapel Hill, NC, 27599, USA.
Katherine S PollardGladstone Institute of Data Science and Biotechnology; San Francisco, CA, 94158, USA.
Chunyu LiuDepartment of Psychiatry, SUNY Upstate Medical University; Syracuse, NY, 13210, USA.
Michael J GandalInterdepartmental Program in Bioinformatics, University of California, Los Angeles; Los Angeles, CA, 90095, USA.
University of California, Los Angeles · USJohns Hopkins University · USUniversity of North Carolina at Chapel Hill · USBroad Institute · USYale University · USChildren's Hospital of Philadelphia · USGladstone Institutes · USSUNY Upstate Medical University · USUniversity of Massachusetts Chan Medical School · USCardiff University · GBCentral South University · CNQB3 · USSage Bionetworks · USUniversity of Pittsburgh · US

Funding

Functional Genomics of Human Brain DevelopmentP50MH106934 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2014 to 2019
$7.9M
Cis-Regulatory Epigenome Mappings in SchizophreniaU01MH103392 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI AKBARIAN, SCHAHRAM, SKLAR, PAMELA · 2014 to 2017
$7.6M
Molecular Profiling of SchizophreniaR01MH110921 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI CHESS, ANDREW J, ROUSSOS, PANAGIOTIS · 2016 to 2020
$6.9M
Transcriptional and Epigenetic Signatures of Human Brain Development and AutismU01MH103339 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD, STATE, MATTHEW W. · 2014 to 2017
$6.5M
1/2 Cell Type and Region-Specific Regulatory Networks in Human Brain Development and DisordersU01MH116488 · NIMH · YALE UNIVERSITY · PI SESTAN, NENAD · 2018 to 2022
$6.5M
Discovery and validation of neuronal enhancers as development of psychiatric disorders supplementU01MH116492 · NIMH · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI GERSTEIN, MARK BENDER, WENG, ZHIPING · 2018 to 2023
$6.2M
The 3D genome in transcriptional regulation across the postnatal life span, with implications for schizophrenia and bipolar disorderU01MH116442 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI AKBARIAN, SCHAHRAM, DRACHEVA, STELLA · 2018 to 2022
$5.9M
2/3 Understanding PTSD through Postmortem Targeted Brain Multi-omicsR01MH117291 · NIMH · LIEBER INSTITUTE, INC. · PI Joel Edward Kleinman · 2018 to 2026
$5.2M
Site 3/3, Understanding PTSD through Postmortem Targeted Brain MultiomicsR01MH117292 · NIMH · MCLEAN HOSPITAL · PI Nikolaos Daskalakis, KERRY J. RESSLER · 2018 to 2026
$5.0M
Dynamic RNA Modifications in human brain development and autismU01MH116441 · NIMH · EMORY UNIVERSITY · PI JIN, PENG · 2018 to 2022
$4.9M
Risk genetic variants and cis regulation of gene expression in Bipolar DisorderR01MH109677 · NIMH · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI ROUSSOS, PANAGIOTIS · 2016 to 2020
$4.6M
Sex-specific trajectories in epigenomic regulation of brain patterningR01MH129301 · NIMH · YALE UNIVERSITY · PI FLORA M VACCARINO · 2022 to 2026
$4.5M
NIDA NIH HHS U01 DA048279NIMH NIH HHS P50 MH106934NIMH NIH HHS R01 MH094714NIMH NIH HHS R01 MH105472NIMH NIH HHS R01 MH105898NIMH NIH HHS R01 MH109677NIMH NIH HHS R01 MH109715NIMH NIH HHS R01 MH110905NIMH NIH HHS R01 MH110920NIMH NIH HHS R01 MH110921NIMH NIH HHS R01 MH110926NIMH NIH HHS R01 MH110927NIMH NIH HHS R01 MH110928NIMH NIH HHS R01 MH111721NIMH NIH HHS R01 MH116529NIMH NIH HHS R01 MH117291NIMH NIH HHS R01 MH117292NIMH NIH HHS R01 MH117293NIMH NIH HHS R01 MH117406NIMH NIH HHS R01 MH118349NIMH NIH HHS R01 MH121521NIMH NIH HHS R01 MH123922NIMH NIH HHS R01 MH125516NIMH NIH HHS R01 MH126393NIMH NIH HHS R01 MH126459NIMH NIH HHS R01 MH129301NIMH NIH HHS R01 MH137578NIMH NIH HHS R21 MH102791NIMH NIH HHS R21 MH103877NIMH NIH HHS R21 MH105853NIMH NIH HHS R21 MH105881NIMH NIH HHS R21 MH109956NIMH NIH HHS R21 MH129817NIMH NIH HHS R56 MH114899NIMH NIH HHS R56 MH114901NIMH NIH HHS R56 MH114911NIMH NIH HHS U01 MH103339NIMH NIH HHS U01 MH103340NIMH NIH HHS U01 MH103346NIMH NIH HHS U01 MH103365NIMH NIH HHS U01 MH103392NIMH NIH HHS U01 MH116438NIMH NIH HHS U01 MH116441NIMH NIH HHS U01 MH116442NIMH NIH HHS U01 MH116487NIMH NIH HHS U01 MH116488NIMH NIH HHS U01 MH116489NIMH NIH HHS U01 MH116492NIMH NIH HHS U01 MH122509NIMH NIH HHS U01 MH122590NIMH NIH HHS U01 MH122591NIMH NIH HHS U01 MH122592NIMH NIH HHS U01 MH122678NIMH NIH HHS U01 MH122681NIMH NIH HHS U01 MH122849
6 · The paper itself

Abstract

Genomic regulatory elements active in the developing human brain are notably enriched in genetic risk for neuropsychiatric disorders, including autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. However, prioritizing the specific risk genes and candidate molecular mechanisms underlying these genetic enrichments has been hindered by the lack of a single unified large-scale gene regulatory atlas of human brain development. Here, we uniformly process and systematically characterize gene, isoform, and splicing quantitative trait loci (xQTLs) in 672 fetal brain samples from unique subjects across multiple ancestral populations. We identify 15,752 genes harboring a significant xQTL and map 3,739 eQTLs to a specific cellular context. We observe a striking drop in gene expression and splicing heritability as the human brain develops. Isoform-level regulation, particularly in the second trimester, mediates the greatest proportion of heritability across multiple psychiatric GWAS, compared with eQTLs. Via colocalization and TWAS, we prioritize biological mechanisms for ~60% of GWAS loci across five neuropsychiatric disorders, nearly two-fold that observed in the adult brain. Finally, we build a comprehensive set of developmentally regulated gene and isoform co-expression networks capturing unique genetic enrichments across disorders. Together, this work provides a comprehensive view of genetic regulation across human brain development as well as the stage-and cell type-informed mechanistic underpinnings of neuropsychiatric disorders.

Identifiers

PMID36945630
PMCPMC10029021
OpenAlexW4323537255

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.