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

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; Biobank Japan Project; FinnGen Consortium; Chikashi Terao; Hongyu Zhao; Benjamin L Ebert; Muredach P Reilly; Andrea Ganna; Mitchell J Machiela; Giulio Genovese; Pradeep Natarajan

doi:10.1038/s41591-021-01371-0

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

Nat Med. 2021 Jun;27(6):1012-1024. doi: 10.1038/s41591-021-01371-0. Epub 2021 Jun 7.

Authors

Seyedeh M Zekavat^#^{1

2

3}, Shu-Hong Lin^#⁴, Alexander G Bick^{2

5}, Aoxing Liu⁶, Kaavya Paruchuri^{2

3

7}, Chen Wang^{8

9}, Md Mesbah Uddin^{2

3}, Yixuan Ye¹, Zhaolong Yu¹, Xiaoxi Liu¹⁰, Yoichiro Kamatani¹⁰, Romit Bhattacharya³, James P Pirruccello^{2

3

7}, Akhil Pampana^{2

3}, Po-Ru Loh^{2

7}, Puja Kohli^{11

12}, Steven A McCarroll^{13

14}, Krzysztof Kiryluk^{9

15}, Benjamin Neale^{13

16}, Iuliana Ionita-Laza⁸, Eric A Engels¹⁷, Derek W Brown⁴, Jordan W Smoller^{13

18

19}, Robert Green^{2

7

14}, Elizabeth W Karlson^{7

20}, Matthew Lebo^{21

22}, Patrick T Ellinor^{2

3

7}, Scott T Weiss^{7

23}, Mark J Daly⁶; Biobank Japan Project; FinnGen Consortium; Chikashi Terao^{10

24

25}, Hongyu Zhao^{1

26}, Benjamin L Ebert^{2

27

28}, Muredach P Reilly^{15

29}, Andrea Ganna^{2

6

16}, Mitchell J Machiela⁴, Giulio Genovese^{2

13

14}, Pradeep Natarajan^{30

31

32}

Collaborators

Satoshi Koyama, Kaoru Ito, Yukihide Momozawa, Koichi Matsuda, Yuji Yamanashi, Yoichi Furukawa, Takayuki Morisaki, Yoshinori Murakami, Kaori Muto, Akiko Nagai, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Sinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Aarno Palotie, Adam Ziemann, Adele Mitchell, Adriana Huertas-Vazquez, Aino Salminen, Airi Jussila, Aki Havulinna, Alex Mackay, Ali Abbasi, Amanda Elliott, Amy Cole, Anastasia Shcherban, Anders Mälarstig, Andrea Ganna, Andrey Loboda, Anna Podgornaia, Anne Lehtonen, Anne Pitkäranta, Anne Remes, Annika Auranen, Antti Hakanen, Antti Palomäki, Anu Jalanko, Anu Loukola, Aparna Chhibber, Apinya Lertratanakul, Arto Lehisto, Arto Mannermaa, Åsa Hedman, Audrey Chu, Aviv Madar, Awaisa Ghazal, Benjamin Challis, Benjamin Sun, Beryl Cummings, Bridget Riley-Gillis, Caroline Fox, Chia-Yen Chen, Clarence Wang, Clement Chatelain, Daniel Gordin, Danjuma Quarless, Danny Oh, David Choy, David Close, David Pulford, David Rice, Dawn Waterworth, Deepak Rajpal, Denis Baird, Dhanaprakash Jambulingam, Diana Chang, Diptee Kulkarni, Dirk Paul, Dongyu Liu, Edmond Teng, Eero Punkka, Eeva Ekholm, Eeva Kangasniemi, Eija Laakkonen, Eleonor Wigmore, Elina Järvensivu, Elina Kilpeläinen, Elisabeth Widen, Ellen Tsai, Elmutaz Mohammed, Erich Strauss, Erika Kvikstad, Esa Pitkänen, Essi Kaiharju, Ethan Xu, Fanli Xu, Fedik Rahimov, Felix Vaura, Franck Auge, Georg Brein, Glenda Lassi, Graham Heap, Hannele Laivuori, Hannele Mattsson, Hannele Uusitalo-Järvinen, Hannu Kankaanranta, Hannu Uusitalo, Hao Chen, Harri Siirtola, Heikki Joensuu, Heiko Runz, Heli Lehtonen, Henrike Heyne, Hilkka Soininen, Howard Jacob, Hubert Chen, Huei-Yi Shen, Huilei Xu, Iida Vähätalo, Ilkka Kalliala, Ioanna Tachmazidou, Jaakko Kaprio, Jaakko Parkkinen, Jaison Jacob, Janet Kumar, Janet van Adelsberg, Jari Laukkanen, Jarmo Ritari, Javier Garcia-Tabuenca, Jeffrey Waring, Jennifer Schutzman, Jimmy Liu, Jiwoo Lee, Joanna Betts, Joel Rämö, Johanna Huhtakangas, Johanna Mäkelä, Johanna Mattson, Johanna Schleutker, Johannes Kettunen, John Eicher, Jonas Zierer, Jonathan Chung, Joni A Turunen, Jorge Esparza Gordillo, Joseph Maranville, Juha Karjalainen, Juha Mehtonen, Juha Rinne, Juha Sinisalo, Juhani Junttila, Jukka Koskela, Jukka Partanen, Jukka Peltola, Julie Hunkapiller, Jussi Pihlajamäki, Justin Wade, Juulia Partanen, Kaarin Mäkikallio, Kai Kaarniranta, Kaisa Tasanen, Kaj Metsärinne, Kalle Pärn, Karen S King, Kari Eklund, Kari Linden, Kari Nieminen, Katariina Hannula-Jouppi, Katherine Call, Katherine Klinger, Kati Donner, Kati Hyvärinen, Kati Kristiansson, Katja Kivinen, Katri Kaukinen, Katri Pylkäs, Katrina de Lange, Keith Usiskin, Kimmo Palin, Kirill Shkura, Kirsi Auro, Kirsi Kalpala, Kirsi Sipilä, Klaus Elenius, Kristin Tsuo, L Elisa Lahtela, Laura Addis, Laura Huilaja, Laura Kotaniemi-Talonen, Laura Mustaniemi, Laura Pirilä, Laure Morin-Papunen, Lauri Aaltonen, Leena Koulu, Liisa Suominen, Lila Kallio, Linda McCarthy, Liu Aoxing, Lotta Männikkö, Maen Obeidat, Manuel Rivas, Marco Hautalahti, Margit Pelkonen, Mari Kaunisto, Mari E Niemi, Maria Siponen, Marika Crohns, Marita Kalaoja, Marja Luodonpää, Marja Vääräsmäki, Marja-Riitta Taskinen, Marjo Tuppurainen, Mark J Daly, Mark McCarthy, Markku Laakso, Markku Laukkanen, Markku Voutilainen, Markus Juonala, Markus Perola, Marla Hochfeld, Martti Färkkilä, Mary Pat Reeve, Masahiro Kanai, Matt Brauer, Matthias Gossel, Matti Peura, Meg Ehm, Melissa Miller, Mengzhen Liu, Mervi Aavikko, Miika Koskinen, Mika Helminen, Mika Kähönen, Mikko Arvas, Mikko Hiltunen, Mikko Kiviniemi, Minal Caliskan, Minna Karjalainen, Minna Raivio, Mirkka Koivusalo, Mitja Kurki, Mutaamba Maasha, Nan Bing, Natalie Bowers, Neha Raghavan, Nicole Renaud, Niko Välimäki, Nina Hautala, Nina Mars, Nina Pitkänen, Nizar Smaoui, Oili Kaipiainen-Seppänen, Olli Carpén, Oluwaseun A Dada, Onuralp Soylemez, Oskari Heikinheimo, Outi Tuovila, Outi Uimari, Padhraig Gormley, Päivi Auvinen, Päivi Laiho, Päivi Mäntylä, Päivi Polo, Paola Bronson, Paula Kauppi, Peeter Karihtala, Pekka Nieminen, Pentti Tienari, Petri Virolainen, Pia Isomäki, Pietro Della Briotta Parolo, Pirkko Pussinen, Priit Palta, Raimo Pakkanen, Raisa Serpi, Rajashree Mishra, Reetta Hinttala, Reetta Kälviäinen, Regis Wong, Relja Popovic, Richard Siegel, Riitta Lahesmaa, Risto Kajanne, Robert Graham, Robert Plenge, Robert Yang, Roosa Kallionpää, Ruoyu Tian, Russell Miller, Sahar Esmaeeli, Saila Kauppila, Sally John, Sami Heikkinen, Sami Koskelainen, Samir Wadhawan, Sampsa Pikkarainen, Samuel Heron, Samuli Ripatti, Sanna Seitsonen, Sanni Lahdenperä, Sanni Ruotsalainen, Sarah Pendergrass, Sarah Smith, Sauli Vuoti, Shabbeer Hassan, Shameek Biswas, Shuang Luo, Sina Rüeger, Sini Lähteenmäki, Sirkku Peltonen, Sirpa Soini, Slavé Petrovski, Soumitra Ghosh, Stefan McDonough, Stephanie Loomis, Steven Greenberg, Susan Eaton, Susanna Lemmelä, Tai-He Xia, Tarja Laitinen, Taru Tukiainen, Teea Salmi, Teemu Niiranen, Teemu Paajanen, Teijo Kuopio, Terhi Kilpi, Terhi Ollila, Tero Hiekkalinna, Tero Jyrhämä, Terttu Harju, Tiina Luukkaala, Tiinamaija Tuomi, Tim Behrens, Tim Lu, Timo Blomster, Timo P Sipilä, Tom Southerington, Tomi Mäkelä, Tuomo Kiiskinen, Tuomo Mantere, Tuomo Meretoja, Tushar Bhangale, Tuula Salo, Tuuli Sistonen, Ulla Palotie, Ulvi Gursoy, Urho Kujala, Valtteri Julkunen, Veikko Salomaa, Veli-Matti Kosma, Venkat Subramaniam Rathinakannan, Venla Kurra, Vesa Aaltonen, Victor Neduva, Vincent Llorens, Vishal Sinha, Vuokko Anttonen, Wei Zhou, Wilco Fleuren, Xing Chen, Xinli Hu, Ying Wu, Yunfeng Huang

Affiliations

¹ Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
² Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
⁴ Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
⁵ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁶ Institute for Molecular Medicine Finland, Helsinki, Finland.
⁷ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, NY, USA.
⁹ Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
¹⁰ Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
¹¹ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹² Vertex Pharmaceuticals, Boston, MA, USA.
¹³ Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁴ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁵ Irving Institute for Clinical and Translational Research, Columbia University, New York City, NY, USA.
¹⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
¹⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Department of Psychiatry, Harvard Medical School, Boston, MA, USA.
²⁰ Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Boston, MA, USA.
²¹ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
²² Laboratory for Molecular Medicine, Partners Healthcare, Cambridge, MA, USA.
²³ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁴ Clinical Research Center, Shizuoka General Hospital, Shizuoka, Japan.
²⁵ The Department of Applied Genetics, The School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
²⁶ Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
²⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
²⁸ Howard Hughes Medical Institute, Boston, MA, USA.
²⁹ Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
³⁰ Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
³¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. [email protected].
³² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

Abstract

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^-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10^-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10^-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10^-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10^-4). 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.

Publication types

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

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Aging / genetics*
Aging / pathology
Biological Specimen Banks
Chromosome Aberrations
Communicable Diseases / complications
Communicable Diseases / genetics*
Communicable Diseases / microbiology
Digestive System Diseases / epidemiology
Digestive System Diseases / genetics
Digestive System Diseases / microbiology
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Hematologic Neoplasms / complications
Hematologic Neoplasms / genetics
Hematologic Neoplasms / microbiology
Humans
Male
Middle Aged
Mosaicism
Pneumonia / epidemiology
Pneumonia / genetics*
Pneumonia / microbiology
Risk Factors
Sepsis / epidemiology
Sepsis / genetics*
Sepsis / microbiology
Urogenital Abnormalities / epidemiology
Urogenital Abnormalities / genetics
Urogenital Abnormalities / microbiology
Young Adult

Supplementary concepts

Genitourinary Tract Anomalies

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding