Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selection.

Journal

medRxiv : the preprint server for health sciences
Titre abrégé: medRxiv
Pays: United States
ID NLM: 101767986

Informations de publication

Date de publication:
31 Jan 2023
Historique:
pubmed: 14 2 2023
medline: 14 2 2023
entrez: 13 2 2023
Statut: epublish

Résumé

Mosaic loss of the X chromosome (mLOX) is the most commonly occurring clonal somatic alteration detected in the leukocytes of women, yet little is known about its genetic determinants or phenotypic consequences. To address this, we estimated mLOX in >900,000 women across eight biobanks, identifying 10% of women with detectable X loss in approximately 2% of their leukocytes. Out of 1,253 diseases examined, women with mLOX had an elevated risk of myeloid and lymphoid leukemias and pneumonia. Genetic analyses identified 49 common variants influencing mLOX, implicating genes with established roles in chromosomal missegregation, cancer predisposition, and autoimmune diseases. Complementary exome-sequence analyses identified rare missense variants in

Identifiants

DOI: 10.1101/2023.01.28.23285140 PMID: 36778285 PMC: PMC9915812
pubmed: 36778285
doi: 10.1101/2023.01.28.23285140
pmc: PMC9915812
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NIEHS NIH HHS
ID : DP2 ES030554
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH104964
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH123451
Pays : United States

Auteurs

Aoxing Liu (A)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
These authors contributed equally: Aoxing Liu, Giulio Genovese, Yajie Zhao.

Giulio Genovese (G)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.
These authors contributed equally: Aoxing Liu, Giulio Genovese, Yajie Zhao.

Yajie Zhao (Y)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
These authors contributed equally: Aoxing Liu, Giulio Genovese, Yajie Zhao.

Matti Pirinen (M)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Department of Publich Health, University of Helsinki, Helsinki, Finland.
Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.

Maryam M Zekavat (MM)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Katherine Kentistou (K)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Zhiyu Yang (Z)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Kai Yu (K)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Caitlyn Vlasschaert (C)

Department of Medicine, Queen's University, Kingston, ON, Canada.

Xiaoxi Liu (X)

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Derek W Brown (DW)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA.

Georgi Hudjashov (G)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Bryan Gorman (B)

Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
Booz Allen Hamilton, McLean, VA, USA.

Joe Dennis (J)

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Weiyin Zhou (W)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Yukihide Momozawa (Y)

Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Saiju Pyarajan (S)

Center for Data and Computational Sciences (C-DACS), VA Cooperative Studies Program, VA Boston Healthcare System, Boston, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Vlad Tuzov (V)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Fanny-Dhelia Pajuste (FD)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Mervi Aavikko (M)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Timo P Sipilä (TP)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Awaisa Ghazal (A)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Wen-Yi Huang (WY)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Neal Freedman (N)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Lei Song (L)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Eugene J Gardner (EJ)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Vijay G Sankaran (VG)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Aarno Palotie (A)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Hanna M Ollila (HM)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
Center of Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Taru Tukiainen (T)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Stephen J Chanock (SJ)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Reedik Mägi (R)

Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.

Pradeep Natarajan (P)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
Center of Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Mark J Daly (MJ)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Alexander Bick (A)

Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Steven A McCarroll (SA)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Department of Genetics, Harvard Medical School, Boston, MA, USA.

Chikashi Terao (C)

Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
Department of Applied Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Po-Ru Loh (PR)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
These authors jointly supervised this work: Po-Ru Loh, Andrea Ganna, John R.B. Perry, Mitchell J. Machiela.

Andrea Ganna (A)

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
These authors jointly supervised this work: Po-Ru Loh, Andrea Ganna, John R.B. Perry, Mitchell J. Machiela.

John R B Perry (JRB)

MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
These authors jointly supervised this work: Po-Ru Loh, Andrea Ganna, John R.B. Perry, Mitchell J. Machiela.

Mitchell J Machiela (MJ)

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
These authors jointly supervised this work: Po-Ru Loh, Andrea Ganna, John R.B. Perry, Mitchell J. Machiela.

Classifications MeSH