Evidence map›Paper›PMID 36042188›Full record

ArticleNature communications2022

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Jennifer L Halford, Valerie N Morrill, Seung Hoan Choi, Sean J Jurgens, Giorgio Melloni, Nicholas A Marston, Lu-Chen Weng, Victor Nauffal, Amelia W Hall, Sophia Gunn and 35 more

Erratum issuedAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 6 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed, 1 pooled it
–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

6 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Article
  6. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

45 authors.

Jennifer L Halford *Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1454-3650
Valerie N Morrill *Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Seung Hoan ChoiCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2797-3190
Sean J JurgensCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1605-9782
Giorgio MelloniTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Nicholas A MarstonTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Lu-Chen WengCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-1475-4930
Victor NauffalCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-7199-299X
Amelia W HallGene Regulation Observatory and Epigenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sophia GunnDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
Christina A Austin-TseLaboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, MA, USA.
James P PirruccelloCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-6088-4037
Shaan KhurshidCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Heidi L RehmCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Emelia J BenjaminNHLBI and Boston University's Framingham Heart Study, Framingham, MA, USA.ORCID http://orcid.org/0000-0003-4076-2336
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Jennifer A BrodyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0001-8509-148X
Adolfo CorreaDepartments of Medicine, Pediatrics and Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA.ORCID http://orcid.org/0000-0002-9501-600X
Brandon K FornwaltDepartment of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
Namrata GuptaCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Christopher M HaggertyDepartment of Translational Data Science and Informatics, Geisinger, Danville, PA, USA.
Stephanie HarrisCardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Susan R HeckbertCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7100-512X
Charles C HongUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.ORCID http://orcid.org/0000-0002-0424-8252
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7986-8560
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.ORCID http://orcid.org/0000-0001-6771-0486
Ruth J F LoosThe Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, 10029, New York, NY, USA.ORCID http://orcid.org/0000-0002-8532-5087
Braxton D MitchellUniversity of Maryland School of Medicine, Baltimore, Maryland, USA.
Alanna C MorrisonHuman Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas, USA.ORCID http://orcid.org/0000-0001-6381-4296
Wendy PostDivision of Cardiology, Johns Hopkins Medicine, Baltimore, MD, USA.
Bruce M PsatyCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7278-2190
Susan RedlineDepartment of Medicine, Brigham and Women's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-6585-1610
Kenneth M RiceDepartment of Biostatistics, University of Washington, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-3071-7278
Stephen S RichCenter for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-3872-7793
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.
Peter F SchnatzDepartment of ObGyn, The Reading Hospital of Tower Health, Reading, PA, USA.
Elsayed Z SolimanEpidemiological Cardiology Research Center, Wake Forest School of Medicine, Winston Salem, NC, USA.ORCID http://orcid.org/0000-0001-5632-8150
Nona SotoodehniaCardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Eugene K WongCardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Marc S SabatineTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Christian T RuffTIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Kathryn L LunettaDepartment of Biostatistics, Boston University School of Public Health, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9268-810X
Patrick T EllinorCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-2067-0533
Steven A LubitzCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA. slubitz@mgh.harvard.edu.ORCID http://orcid.org/0000-0002-9599-4866

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3M
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
WOMEN'S HEALTH INITIATIVE - CLINICAL COORDINATING CENTER: TASK AREA B - LONG LIFE STUDY VISIT 2 LIMITED HOME VISIT75N92021D00001 · NHLBI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI ANDERSON, GARNET L. · 2021 to 2025
$52.0M
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
FRAMINGHAM HEART STUDY - YEAR 5 EXAM75N92019D00031 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · 2019 to 2024
$29.8M
Clinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2M
IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6M
SUBCLINICAL CARDIOVASCULAR DISEASE COORDINATING CENTERN01HC95159 · NHLBI · UNIVERSITY OF WASHINGTON · PI KRONMAL, RICHARD A · 2007 to 2014
$19.6M
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
UCLA CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTEUL1RR033176 · NCRR · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2011 to 2011
$15.5M
Medical Research Council MC_PC_17228Medical Research Council MC_QA137853NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCRR NIH HHS KL2 RR024990NCRR NIH HHS UL1 RR033176NHGRI NIH HHS U01 HG007417NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG003273NHLBI NIH HHS 75N92019D00031NHLBI NIH HHS 75N92020D00001NHLBI NIH HHS 75N92020D00002NHLBI NIH HHS 75N92020D00003NHLBI NIH HHS 75N92020D00004NHLBI NIH HHS 75N92020D00005NHLBI NIH HHS 75N92020D00006NHLBI NIH HHS 75N92020D00007NHLBI NIH HHS 75N92021D00001NHLBI NIH HHS 75N92021D00002NHLBI NIH HHS 75N92021D00006NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100037CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS HHSN268201500003INHLBI NIH HHS HHSN268201500014CNHLBI NIH HHS HHSN268201500015CNHLBI NIH HHS HHSN268201700001INHLBI NIH HHS HHSN268201700002INHLBI NIH HHS HHSN268201700003INHLBI NIH HHS HHSN268201700004INHLBI NIH HHS HHSN268201700005INHLBI NIH HHS HHSN268201800001CNHLBI NIH HHS HHSN268201800010INHLBI NIH HHS HHSN268201800011INHLBI NIH HHS HHSN268201800012INHLBI NIH HHS HHSN268201800014INHLBI NIH HHS HHSN268201800015INHLBI NIH HHS K08 HL153950NHLBI NIH HHS K08 HL159346NHLBI NIH HHS K24 HL105780NHLBI NIH HHS N01HC55222NHLBI NIH HHS N01HC85079NHLBI NIH HHS N01HC85080NHLBI NIH HHS N01HC85081NHLBI NIH HHS N01HC85082NHLBI NIH HHS N01HC85083NHLBI NIH HHS N01HC85086NHLBI NIH HHS N01HC95159NHLBI NIH HHS N01HC95160NHLBI NIH HHS N01HC95161NHLBI NIH HHS N01HC95162NHLBI NIH HHS N01HC95163NHLBI NIH HHS N01HC95164NHLBI NIH HHS N01HC95165NHLBI NIH HHS N01HC95166NHLBI NIH HHS N01HC95167NHLBI NIH HHS N01HC95168NHLBI NIH HHS N01HC95169NHLBI NIH HHS N02 HL64278NHLBI NIH HHS R01 HL046380NHLBI NIH HHS R01 HL071051NHLBI NIH HHS R01 HL071205NHLBI NIH HHS R01 HL071250NHLBI NIH HHS R01 HL071251NHLBI NIH HHS R01 HL071258NHLBI NIH HHS R01 HL071259NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL098433NHLBI NIH HHS R01 HL113338NHLBI NIH HHS R01 HL117626NHLBI NIH HHS R01 HL120393NHLBI NIH HHS R01 HL121007NHLBI NIH HHS R01 HL135129NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL157635NHLBI NIH HHS R35 HL135818NHLBI NIH HHS U01 HL072515NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL130114NIA NIH HHS R01 AG023629NIMHD NIH HHS HHSN268201800013IWHI NIH HHS 75N92021D00003WHI NIH HHS 75N92021D00004WHI NIH HHS 75N92021D00005
6 · The paper itself

Abstract

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

Indexed as

EndophenotypesLong QT SyndromeDisease SusceptibilityHumansVirulence

Identifiers

PMID36042188
PMCPMC9427940

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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.