دورية أكاديمية
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Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.

التفاصيل البيبلوغرافية
العنوان: Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.
المؤلفون: Lassen FH; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK. Electronic address: flassen@well.ox.ac.uk., Venkatesh SS; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK., Baya N; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK., Hill B; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK., Zhou W; 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; Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Bloemendal A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Novo Nordisk Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Neale BM; 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; Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Kessler BM; Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK., Whiffin N; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lindgren CM; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK. Electronic address: cecilia.lindgren@wrh.ox.ac.uk., Palmer DS; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Nuffield Department of Population Health, Medical Sciences Division, University of Oxford, Oxford, UK. Electronic address: duncan.stuart.palmer@gmail.com.
المصدر: Cell genomics [Cell Genom] 2024 Jul 10; Vol. 4 (7), pp. 100602. Date of Electronic Publication: 2024 Jun 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier, Inc Country of Publication: United States NLM ID: 9918284260106676 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-979X (Electronic) Linking ISSN: 2666979X NLM ISO Abbreviation: Cell Genom Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [New York] : Elsevier, Inc., [2021]-
مواضيع طبية MeSH: Phenotype* , Biological Specimen Banks* , Heterozygote* , Exome*/genetics, Humans ; United Kingdom/epidemiology ; Genetic Predisposition to Disease ; Pulmonary Disease, Chronic Obstructive/genetics ; Female ; Male ; Filaggrin Proteins ; Genome-Wide Association Study ; Asthma/genetics ; UK Biobank
مستخلص: The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10 -7 ) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10 -8 ). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.
Competing Interests: Declaration of interests B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
التعليقات: Update of: medRxiv. 2023 Jul 03:2023.06.29.23291992. doi: 10.1101/2023.06.29.23291992. (PMID: 37461573)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; INV-024200 United States GATES Bill & Melinda Gates Foundation; K99 HG012222 United States HG NHGRI NIH HHS; P50 HD104224 United States HD NICHD NIH HHS
فهرسة مساهمة: Keywords: bi-allelic; compound heterozygosity; longtudinal; phasing; population genetics; recessive
المشرفين على المادة: 0 (Filaggrin Proteins)
تواريخ الأحداث: Date Created: 20240629 Date Completed: 20240711 Latest Revision: 20240923
رمز التحديث: 20240923
مُعرف محوري في PubMed: PMC11293579
DOI: 10.1016/j.xgen.2024.100602
PMID: 38944039
قاعدة البيانات: MEDLINE
الوصف
تدمد:2666-979X
DOI:10.1016/j.xgen.2024.100602