Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer.

Humans Calcium Channels / genetics Colorectal Neoplasms / genetics Genome, Human Glaucoma / genetics Minisatellite Repeats Polymorphism, Genetic Eukaryotic Initiation Factor-3 / genetics
GWAS VNTR colorectal cancer expression and splicing quantitative trait loci genetic associations genomic structural variation glaucoma imputation tandem repeat variable numbers of tandem repeats

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
17 08 2023
Historique:
received: 04 10 2022
revised: 07 04 2023
accepted: 03 07 2023
pmc-release: 17 08 2024
medline: 21 8 2023
pubmed: 2 8 2023
entrez: 1 8 2023
Statut: ppublish

Résumé

Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.

Identifiants

DOI: 10.1016/j.cell.2023.07.002 PMID: 37527660 PMC: PMC10528368
pubmed: 37527660
pii: S0092-8674(23)00735-3
doi: 10.1016/j.cell.2023.07.002
pmc: PMC10528368
mid: NIHMS1921393
pii:
doi:

Substances chimiques

Calcium Channels 0
TMCO1 protein, human 0
Eukaryotic Initiation Factor-3 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3659-3673.e23

Subventions

Organisme : NHLBI NIH HHS
ID : F31 HL154537
Pays : United States
Organisme : NIMH NIH HHS
ID : F31 MH124393
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG002295
Pays : United States
Organisme : NHLBI NIH HHS
ID : F32 HL160061
Pays : United States
Organisme : NHLBI NIH HHS
ID : K25 HL150334
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG006855
Pays : United States
Organisme : NIEHS NIH HHS
ID : DP2 ES030554
Pays : United States

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Ronen E Mukamel (RE)

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: rmukamel@broadinstitute.org.

Robert E Handsaker (RE)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: handsake@broadinstitute.org.

Maxwell A Sherman (MA)

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.

Alison R Barton (AR)

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Bioinformatics and Integrative Genomics Program, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

Margaux L A Hujoel (MLA)

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Steven A McCarroll (SA)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: smccarro@broadinstitute.org.

Po-Ru Loh (PR)

Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: poruloh@broadinstitute.org.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux calciques › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Maladies de l'oeil › Hypertension oculaire › Glaucome › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Répétitions minisatellites › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Repeat polymorphisms underlie top genetic risk...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines ribosomiques › Facteurs initiation chaîne peptidique › Facteurs d'initiation eucaryotes › Facteur-3 d'initiation eucaryote › Repeat polymorphisms underlie top genetic risk...