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Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer

Abstract

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.

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Fig. 1: Manhattan plots and quantile–quantile plots of the GWAS meta-analysis for lung cancer in the cross-ancestry analyses.
Fig. 2: Functional validation of the prioritized genes from cross-ancestry lung cancer GWASs.
Fig. 3: Dysregulation of cross-ancestry lung cancer GWAS-nominated risk genes promotes DNA damage.

Data availability

The following publicly available datasets were used in this work: dbGaP datasets (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, phs000093.v2.p2; FLCCA study, phs000716.v1.p1; EAGLE study, phs000336.v1.p1; NCI study of African-Americans, phs001210.v1.p1; German, SLRI, IARC and MDACC studies, phs000876.v2.p1; Oncoarray study, phs001273.v3.p2; imputed Oncoarray study using HRC reference panel, phs001273.v4.p2; Affymetrix study, phs001681.v1.p1). The ICR study from the 1958 Birth Cohort from the UK does not allow the general upload of findings. Therefore, this dataset is available after request from R. Houlston (Richard.Houlston@icr.ac.uk). The individual-level genotype and phenotype data are available through formal application to the UKBB (https://www.ukbiobank.ac.uk/). The GWAS summary statistics used in validation study were downloaded from FinnGen (https://finngen.gitbook.io/documentation/v/r5/data-download) and the pan-cancer pleiotropy study (https://github.com/Wittelab/pancancer_pleiotropy). The GWAS summary statistics of the candidate 45 variants identified from the discovery phase were obtained following our request from M.Z. and H.S. (China NJMU lung study), T.R. (deCODE and SPAIN lung study) and A.S. and C.L. (INHALE study) and are available in the Supplementary Tables 9 and 10. The eQTL data from GTEx v8 was obtained from https://gtexportal.org/home/datasets. The Icelandic population WGS genetic but not phenotypic data have been deposited at the European Variant Archive under accession code PRJEB15197. Results from GWMA at P ≤ 10−5 are available in the supplementary tables. All sequencing reads were mapped to the GRCh37/hg19 human reference genome. More details of data sources used in this work are provided in the paper and supplementary tables.

Code availability

We performed our analyses using the following publicly available software/packages: SHAPE-IT2 (v2.r790; https://mathgen.stats.ox.ac.uk/genetics_software/shapeit/shapeit.html), McCarthy Group Tools (v4.2.11; https://www.well.ox.ac.uk/~wrayner/tools/), PBWT (https://github.com/richarddurbin/pbwt) and Michigan Imputation Server (https://imputationserver.sph.umich.edu/index.html#!) were used for imputation and phasing; FastPop (https://github.com/biomedicaldatascience/FastPop4) and KING (v2.0, http://people.virginia.edu/~wc9c/KING/) were used for population stratification and relatedness analyses; SAS (v9.4, https://www.sas.com/en_us/home.html), R (v3.6.2, https://cran.r-project.org), PLINK (v1.9 and 2.0, https://www.cog-genomics.org/plink/1.9/ and https://www.cog-genomics.org/plink/2.0/), METASOFT and ForestPMPlot (v2.0.1 and v1.0.3, http://genetics.cs.ucla.edu/meta/) and GCTA (v1.93, https://cnsgenomics.com/software/gcta/) were used for data and statistical analyses; FUMA (v1.3.6, https://fuma.ctglab.nl/), FAVOR (https://favor.genohub.org/), GTEx (v8, https://www.gtexportal.org/home/), coloc (v3.2-1, https://cran.r-project.org/web/packages/coloc/), eCAVIAR (v2, http://zarlab.cs.ucla.edu/tag/caviar/), IPA (https://www.qiagenbioinformatics.com/products/ingenuity-pathway-analysis) and ezQTL (v1.0, https://analysistools.cancer.gov/ezqtl/#/home) were used for post-GWAS analyses; and FlowJo (v10.6, https://www.flowjo.com) was used for single-cell flow cytometry analysis. MANTRA (version 1) is available as a suite of executables on request from the corresponding author (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460225/pdf/gepi0035-0809.pdf).

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Acknowledgements

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.

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J.B., Y. Han, Y. Li and C.I.A. conceived and designed the study. Y. Han and X.X. acquired the data. Y. Han, E.L., J.C. and X.X. performed the analysis. J.X. and Z.S. performed experimental validation. M.Z., W. Zhou, R.S., A.S., C.L., T.R., L.K. and L.C.S. provided substantial support on validation study. J.B., Y. Han, Y. Li, J.X., E.L., J.C. and C.I.A. interpreted the results. J.B., J.X., E.L. and J.C. wrote the first draft of the manuscript. J.B., Y. Han, J.X., E.L., J.C. and X.X. provided supplementary materials. J.B. and C.I.A. provided supervision and contributed to analyses. All authors reviewed and commented on the manuscript and approved the final version of the manuscript.

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Correspondence to Christopher I. Amos.

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The authors declare no competing interests.

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Nature Genetics thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 LocusZoom regional plots of newly identified cross-ancestry genetic variants.

Newly identified cross-ancestry variant is colored in purple, and colors of other dots indicate linkage disequilibrium measure r2 with the lead variant in purple. a,b, Regional association plots at the CYP8B1 (a) and IRF4 locus (b) in overall lung cancer (Lung). c, Regional association plot at the ACTR2 locus in lung adenocarcinoma (ADE). d, Regional association plot at the LINC01122 locus in lung squamous cell carcinoma (SQC). e, Regional association plot at the IL17RC locus in small cell lung cancer (SCC).

Extended Data Fig. 2 Gating strategies for DNA damage assays.

ac, Gating strategy, associated with Fig. 3a. (d) histograms of γH2AX in EmGFP-FUBP1 and EmGFP-Tubulin overproducing cells. eg, Gating strategy, associated with Fig. 3b. hj, Gating strategy, associated with methods: flow-cytometric DNA damage assays, Q2/Q2 + Q3 calculation in overproduction experiments.

Extended Data Fig. 3 Inference of ancestry membership in three intercontinental populations using FastPop.

The colored points in grey indicate 70,639 individuals from diverse populations. Those in orange, green, and blue denote HapMap 3 samples with European (CEU), East Asian (CHB), African (YRI) ancestry, respectively.

Supplementary information

Supplementary Information

Supplementary Note, Tables 25 and 26 and Figs. 1–4.

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Supplementary Tables

Supplementary Tables 1–24.

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Byun, J., Han, Y., Li, Y. et al. Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer. Nat Genet 54, 1167–1177 (2022). https://doi.org/10.1038/s41588-022-01115-x

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