Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer
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To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Genetics |
| Vol/bind | 54 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1167-1177 |
| Antal sider | 11 |
| ISSN | 1061-4036 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
Our study was supported by the National Institutes of Health (NIH) for Integrative Analysis of Lung Cancer Etiology and Risk (U19CA203654) and Sequencing Familial Lung Cancer (R01CA243483). C.I.A. is a Research Scholar of the Cancer Prevention Research Interest of Texas (CPRIT) award (RR170048). Functional studies were partially supported by NIH grants (R01CA250905 (S.M.R), CPRIT RR170048 (C.I.A) and DP1-AG072751 (S.M.R.)). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT RP180672) and the NIH (CA125123 and RR024574) as well as the assistance of J.M. Sederstrom. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. D.M. was supported by Department of Health and Human Services contracts HHSN26820100007C, HHSN268201700012C and 75N92020C00001. J.E.B. was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. R.W.P. was supported by NIH T32ES027801. J.X. was supported by the National Institute of Environmental Health Sciences of the NIH under Award Number K99ES033259. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. We acknowledge the participants and investigators of INTEGRAL-ILCCO Consortium, Genetic Epidemiology of Lung Cancer Consortium (GELCC), FinnGen study and Kaiser Permanente Research Bank (KPRB) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort study.
Funding Information:
Our study was supported by the National Institutes of Health (NIH) for Integrative Analysis of Lung Cancer Etiology and Risk (U19CA203654) and Sequencing Familial Lung Cancer (R01CA243483). C.I.A. is a Research Scholar of the Cancer Prevention Research Interest of Texas (CPRIT) award (RR170048). Functional studies were partially supported by NIH grants (R01CA250905 (S.M.R), CPRIT RR170048 (C.I.A) and DP1-AG072751 (S.M.R.)). This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT RP180672) and the NIH (CA125123 and RR024574) as well as the assistance of J.M. Sederstrom. The Resource for the Study of Lung Cancer Epidemiology in North Trent (ReSoLuCENT) study was funded by the Sheffield Hospitals Charity, Sheffield Experimental Cancer Medicine Centre and Weston Park Hospital Cancer Charity. F.T. was supported by a clinical PhD fellowship funded by the Yorkshire Cancer Research/Cancer Research UK Sheffield Cancer Centre. D.M. was supported by Department of Health and Human Services contracts HHSN26820100007C, HHSN268201700012C and 75N92020C00001. J.E.B. was supported by the Intramural Research Program of the National Human Genome Research Institute, NIH. R.W.P. was supported by NIH T32ES027801. J.X. was supported by the National Institute of Environmental Health Sciences of the NIH under Award Number K99ES033259. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. We acknowledge the participants and investigators of INTEGRAL-ILCCO Consortium, Genetic Epidemiology of Lung Cancer Consortium (GELCC), FinnGen study and Kaiser Permanente Research Bank (KPRB) Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort study.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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