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.
| Original language | English |
|---|---|
| Article number | 19365 |
| Journal | Scientific Reports |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 29 Sept 2021 |
Bibliographical note
Funding Information: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 to [15].
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© 2021, The Author(s).