Evidence map›Paper›PMID 37868038›Full record

ArticleCell genomics2023

The functional impact of rare variation across the regulatory cascade.

Taibo Li, Nicole Ferraro, Benjamin J Strober, Francois Aguet, Silva Kasela, Marios Arvanitis, Bohan Ni, Laurens Wiel, Elliot Hershberg, Kristin Ardlie and 28 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell genomics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.

0numbers the graph read from it
0cells of the map it votes in
13citing 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

13 citing papers in PubMed.

  1. Review
  2. Article
  3. Population-scale detection of methylation outliers from long-read genome sequencing.medRxiv : the preprint server for health sciences · 2026
    Article
  4. Article
  5. Long-read genome sequencing and multi-omics in aging and neurodegeneration.medRxiv : the preprint server for health sciences · 2025
    Article
  6. Article
  7. Article
  8. Article
  9. Exome sequencing identifies genes for socioeconomic status in 350,770 individuals.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
  10. Article
  11. Review
  12. Article
  13. Article
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

38 authors.

Taibo LiDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Nicole FerraroBiomedical Informatics Training Program, Stanford University, Stanford, CA, USA.
Benjamin J StroberDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Francois AguetBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Silva KaselaNew York Genome Center, New York, NY, USA.
Marios ArvanitisDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bohan NiDepartment of Computer Science, Johns Hopkins University, Baltimore, MD, USA.
Laurens WielDivision of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Elliot HershbergDepartment of Genetics, Stanford University, Stanford, CA, USA.
Kristin ArdlieBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Dan E ArkingMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Rebecca L BeerNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Jennifer BrodyCardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
Thomas W BlackwellDepartment of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Clary ClishBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Stacey GabrielBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Robert GersztenBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Namrata GuptaBroad Institute of MIT and Harvard, Cambridge, MA, USA.
W Craig JohnsonCollaborative Health Studies Coordinating Center, University of Washington, Seattle, WA, USA.
Tuuli LappalainenNew York Genome Center, New York, NY, USA.
Henry J LinThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Yongmei LiuDepartment of Medicine, Duke University School of Medicine, Durham, NC, USA.
Deborah A NickersonDepartment of Genome Sciences, University of Washington, Seattle, WA, USA.
George PapanicolaouNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Jonathan K PritchardDepartment of Genetics and Biology, Stanford University, Palo Alto, CA, USA.
Pankaj QasbaNational Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Ali ShojaieDepartment of Biostatistics, University of Washington School of Public Health, Seattle, WA, USA.
Josh SmithDepartment of Genome Sciences, University of Washington, Seattle, WA, USA.
Nona SotoodehniaCardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Russell P TracyLaboratory for Clinical Biochemistry Research, University of Vermont, Burlington, VT, USA.
David Van Den BergDepartment of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
Matthew T WheelerDivision of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Alexis BattleDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Stephen B MontgomeryDepartment of Genetics, Stanford University, Stanford, CA, USA.

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1M
Institute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1M
Transgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MILES Frome WILKINSON · 2003 to 2026
$40.4M
Wake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3M
ROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Elizabeth Austen Lawson, Takara Leah Stanley · 1994 to 2026
$31.6M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
Task Area A Core Study Operations.Task Area A shall encompass annual follow-up of cohort members, clinical endpoints ascertainment, study coordination activities, maintenance of the database and biosp75N92020D00001 · NHLBI · UNIVERSITY OF WASHINGTON · PI MCCLELLAND, ROBYN LEAGH · 2020 to 2025
$17.2M
Medical Scientist Training ProgramT32GM136577 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI ANDREA L COX · 2020 to 2026
$13.4M
Studies of Rare Genetic Variation in the Isolated Population of SardiniaR01HL117626 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ABECASIS, GONCALO · 2013 to 2016
$10.5M
Rare variants and NHLBI traits in deeply phenotyped cohortsR01HL120393 · NHLBI · UNIVERSITY OF WASHINGTON · PI PSATY, BRUCE M, RICE, KENNETH M. · 2014 to 2016
$8.9M
Task Area A shall encompass annual follow-up of cohort members, clinical events investigations, study operations, and data analysis and manuscript writing. If implemented, Task A.1 will provide fundin75N92020D00005 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI WATSON, KAROL E · 2020 to 2025
$5.1M
NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NHGRI NIH HHS U01 HG009431NHGRI NIH HHS U54 HG003067NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL141989NHLBI NIH HHS R01 HL142015NIA NIH HHS R01 AG066490NIDDK NIH HHS P30 DK040561NIDDK NIH HHS P30 DK063491NIGMS NIH HHS R35 GM139580NIGMS NIH HHS T32 GM136577NIMH NIH HHS R01 MH125244
6 · The paper itself

Abstract

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.

Indexed as

functional genomicsmachine learningmethylomemulti-omicsproteomerare variantstranscriptome

Identifiers

PMID37868038
PMCPMC10589633

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.