University of Oulu

Yang, T., Jackson, V.E., Smith, A.V. et al. Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function. Sci Rep 11, 19365 (2021). https://doi.org/10.1038/s41598-021-98120-7

Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

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Author: Yang, Tianzhong1,2; Jackson, Victoria E.3; Smith, Albert V.4;
Organizations: 1Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
2Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA
3Department of Health Sciences, University of Leicester, Leicester, UK
4Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
5Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
6Center for Precision Health, School of Public Health and School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA
7Department of Biostatistics, University of Washington, Seattle, USA
8Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
9Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA
10Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
11Division of Pulmonary, Critical Care, and Sleep, Department of Medicine, University of Washington, Seattle, WA, USA
12Department of Medicine, Pulmonary Center, Boston University School of Medicine, Boston, MA, USA
13National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA
14Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
15Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
17Division of Cardiology, Department of Medicine, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA
18Sticht Center for Healthy Aging and Alzheimer’s Prevention, Wake Forest School of Medicine, Winston-Salem, NC, USA
19Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, NY, USA
20Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
21Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
22Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Ludwig-Maximilians-Universität, Munich, Germany
23Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany
24Institute for Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany
25Department of Psychology, The University of Edinburgh, Edinburgh, UK
26Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK
27Alzheimer Scotland Dementia Research Centre, The University of Edinburgh, Edinburgh, UK
28Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
29Division of Biostatistics and Epidemiology, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
30Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
31Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
32Department of Medicine, Department of Epidemiology, Columbia University Medical Center, New York, NY, USA
33David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
34Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
35Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
36Division of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
37Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
38Faculty of Medicine, Center for Life Course Health Research, University of Oulu, Oulu, Finland
39Biocenter of Oulu, University of Oulu, Oulu, Finland
40Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands
41Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
42Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
43DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany
44Division of Cardiology, Pneumology, Infectious Diseases, Intensive Care Medicine, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
45Department of Internal Medicine, Vivantes Hospital Berlin Spandau, Berlin, Germany
46Division of Respiratory Medicine, University of Nottingham, Nottingham, UK
47Leicester Respiratory Biomedical Research Unit, National Institute for Health Research, Glenfield Hospital, Leicester, UK
48Department of Health and Human Services, Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA
49Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021112456839
Language: English
Published: Springer Nature, 2021
Publish Date: 2021-11-24
Description:

Abstract

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV₁), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV₁. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

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Series: Scientific reports
ISSN: 2045-2322
ISSN-E: 2045-2322
ISSN-L: 2045-2322
Volume: 11
Issue: 1
Article number: 19365
DOI: 10.1038/s41598-021-98120-7
OADOI: https://oadoi.org/10.1038/s41598-021-98120-7
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Subjects:
Funding: We gratefully acknowledge the contribution of LBC1936 co-author Professor John M. Starr, who died prior to the publication of this manuscript. Drs. Yang, Morrison and Wei were supported by the NIH Grant R21HL126032; Dr. London was supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences (Z01 ES43012); Dr. Manichaikul was supported by NIH Grant R01 HL131565. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. MESA Family is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071258, R01HL071259, by the National Center for Research Resources, Grant UL1RR033176, and the National Center for Advancing Translational Sciences, Grant UL1TR001881. The MESA Lung study was supported by grants R01 HL077612, R01 HL093081 and RC1 HL100543 from the NHLBI. This publication was developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S Environmental protection Agency. It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Health, Aging, and Body Composition (Health ABC) was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, and in part by the Intramural Research Program of NIA. This work was also supported, in part, by Intramural Research Programs of the NHGRI. The genome-wide association study in Health ABC was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through an NIH contract to The Johns Hopkins University (HHSN268200782096C). This research was further supported by RC1AG035835. Phenotype collection in the LBC1936 was supported by Age UK (The Disconnected Mind project). Genotyping was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, and the Royal Society of Edinburgh. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council (MRC) is gratefully acknowledged. M.D. Tobin is supported by a Wellcome Trust Investigator Award (WT202849/Z/16/Z). M.D. Tobin has been supported by the MRC (MR/N011317/1). The research was partially supported by the NIHR Leicester Biomedical Research Centre; the views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 07/18/21. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195, HHSN268201500001I and 75N92019D00031). Genotyping, quality control and calling of the Illumina HumanExome BeadChip in the Framingham Heart Study was supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O’Donnell, Principle Investigators). The Rotterdam Study is funded by Erasmus MC and Erasmus University Rotterdam; the Netherlands Organisation for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. This work was supported by the Fund for Scientific Research Flanders (FWO) project (3G037618). The Atherosclerosis Risk in Communities study (ARIC) has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). For acknowledgements to other participating cohorts (AGES, 1985BC, NFBC1966, SHIP, CHS, NEO, KORA, UK BioBank and UK Believe), please refer to15.
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