Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases.

Humans Multifactorial Inheritance / genetics Quantitative Trait Loci / genetics Genome-Wide Association Study / methods Genetic Predisposition to Disease / genetics Phenotype Polymorphism, Single Nucleotide / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
08 2023
Historique:
received: 14 08 2020
accepted: 09 06 2023
medline: 11 8 2023
pubmed: 14 7 2023
entrez: 13 7 2023
Statut: ppublish

Résumé

Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.

Identifiants

DOI: 10.1038/s41588-023-01443-6 PMID: 37443254
pubmed: 37443254
doi: 10.1038/s41588-023-01443-6
pii: 10.1038/s41588-023-01443-6
doi:

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

1267-1276

Subventions

Organisme : NIH HHS
ID : DP5 OD024582
Pays : United States
Organisme : NHLBI NIH HHS
ID : DP2 HL152423
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK075787
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034854
Pays : United States
Organisme : NHGRI NIH HHS
ID : F31 HG009850
Pays : United States
Organisme : NHGRI NIH HHS
ID : K99 HG009917
Pays : United States
Organisme : NHGRI NIH HHS
ID : R00 HG009917
Pays : United States

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Elle M Weeks (EM)

Broad Institute of MIT and Harvard, Cambridge, MA, USA. eweeks@broadinstitute.org.
ORCID: 0000-0002-4317-4444

Jacob C Ulirsch (JC)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA.
Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA, USA.
ORCID: 0000-0002-7947-0827

Nathan Y Cheng (NY)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Brian L Trippe (BL)

Program in Computational & Systems Biology, MIT, Cambridge, MA, USA.
Computer Science & Artificial Intelligence Lab, MIT, Cambridge, MA, USA.

Rebecca S Fine (RS)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Vertex Pharmaceuticals Incorporated, Boston, MA, USA.

Jenkai Miao (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.

Tejal A Patwardhan (TA)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Statistics, Harvard University, Cambridge, MA, USA.

Masahiro Kanai (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, MGH, Boston, MA, USA.
Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
ORCID: 0000-0001-5165-4408

Joseph Nasser (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Charles P Fulco (CP)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Bristol Myers Squibb, Cambridge, MA, USA.

Katherine C Tashman (KC)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Francois Aguet (F)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
ORCID: 0000-0001-9414-300X

Taibo Li (T)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
MD-PhD Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
ORCID: 0000-0002-6624-9293

Jose Ordovas-Montanes (J)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA.
Program in Immunology, Harvard Medical School, Boston, MA, USA.
Harvard Stem Cell Institute, Cambridge, MA, USA.

Christopher S Smillie (CS)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Computational & Systems Biology, MIT, Cambridge, MA, USA.

Moshe Biton (M)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Molecular Biology, MGH, Boston, MA, USA.
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.

Alex K Shalek (AK)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Institute for Medical Engineering and Science, MIT, Cambridge, MA, USA.
Department of Chemistry, MIT, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
Ragon Institute of MGH, MMIT, Cambridge, MA, USA.

Ashwin N Ananthakrishnan (AN)

Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.

Ramnik J Xavier (RJ)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Molecular Biology, MGH, Boston, MA, USA.
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Aviv Regev (A)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
Howard Hughes Medical Institute, MIT, Cambridge, MA, USA.
Genentech, San Francisco, CA, USA.
ORCID: 0000-0003-3293-3158

Rajat M Gupta (RM)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Cardiovascular Medicine and Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Kasper Lage (K)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Surgery, MGH, Boston, MA, USA.

Kristin G Ardlie (KG)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

Joel N Hirschhorn (JN)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Eric S Lander (ES)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Biology, MIT, Cambridge, MA, USA.
Department of Systems Biology, Harvard Medical School, Boston, MA, USA.

Jesse M Engreitz (JM)

Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
BASE Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.
ORCID: 0000-0002-5754-1719

Hilary K Finucane (HK)

Broad Institute of MIT and Harvard, Cambridge, MA, USA. finucane@broadinstitute.org.
Analytic and Translational Genetics Unit, MGH, Boston, MA, USA. finucane@broadinstitute.org.
ORCID: 0000-0003-3864-9828

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Leveraging polygenic enrichments of gene...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Leveraging polygenic enrichments of gene...