Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Jun 10, 2021

Contributor: Seyedeh M Zekavat,Shu-Hong Lin,Alexander G Bick,Aoxing Liu,Kaavya Paruchuri,Chen Wang,Md Mesbah Uddin,Yixuan Ye,Zhaolong Yu,Xiaoxi Liu,Yoichiro Kamatani,Romit Bhattacharya,James P Pirruccello,Akhil Pampana,Po-Ru Loh,Puja Kohli,Steven A McCarroll,Krzysztof Kiryluk,Benjamin Neale,Iuliana Ionita-Laza,Eric A Engels,Derek W Brown,Jordan W Smoller,Robert Green,Elizabeth W Karlson,Matthew Lebo,Patrick T Ellinor,Scott T Weiss,Mark J Daly, , ,Chikashi Terao,Hongyu Zhao,Benjamin L Ebert,Muredach P Reilly,Andrea Ganna,Mitchell J Machiela,Giulio Genovese,Pradeep Natarajan

Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.

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Seyedeh M Zekavat

Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Shu-Hong Lin

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

Alexander G Bick

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

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

Aoxing Liu

Institute for Molecular Medicine Finland, Helsinki, Finland.

Kaavya Paruchuri

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Chen Wang

Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, NY, USA.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.

Md Mesbah Uddin

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Yixuan Ye

Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.

Zhaolong Yu

Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.

Xiaoxi Liu

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

Yoichiro Kamatani

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

Romit Bhattacharya

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

James P Pirruccello

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Akhil Pampana

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Po-Ru Loh

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Puja Kohli

Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

Vertex Pharmaceuticals, Boston, MA, USA.

Steven A McCarroll

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

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Krzysztof Kiryluk

Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.

Irving Institute for Clinical and Translational Research, Columbia University, New York City, NY, USA.

Benjamin Neale

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

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Iuliana Ionita-Laza

Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, NY, USA.

Eric A Engels

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

Derek W Brown

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

Jordan W Smoller

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

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Department of Psychiatry, Harvard Medical School, Boston, MA, USA.

Robert Green

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Elizabeth W Karlson

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston, MA, USA.

Matthew Lebo

Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

Laboratory for Molecular Medicine, Partners Healthcare, Cambridge, MA, USA.

Patrick T Ellinor

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Scott T Weiss

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.

Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA.

Mark J Daly

Institute for Molecular Medicine Finland, Helsinki, Finland.

Chikashi Terao

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

Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.

The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

Hongyu Zhao

Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.

Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.

Benjamin L Ebert

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Howard Hughes Medical Institute, Boston, MA, USA.

Muredach P Reilly

Irving Institute for Clinical and Translational Research, Columbia University, New York City, NY, USA.

Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.

Andrea Ganna

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

Institute for Molecular Medicine Finland, Helsinki, Finland.

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.

Mitchell J Machiela

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

Giulio Genovese

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.

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

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Pradeep Natarajan

Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA. pnatarajan@mgh.harvard.edu.

Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. pnatarajan@mgh.harvard.edu.

Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. pnatarajan@mgh.harvard.edu.

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Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.

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