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

  • Sampson, J. N. et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J. Natl Cancer Inst. 107, djv279 (2015).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Bosse, Y. & Amos, C. I. A decade of GWAS results in lung cancer. Cancer Epidemiol. Biomarkers Prev. 27, 363–379 (2018).

    PubMed 
    Article 

    Google Scholar
     

  • Park, S. L., Cheng, I. & Haiman, C. A. Genome-wide association studies of cancer in diverse populations. Cancer Epidemiol. Biomarkers Prev. 27, 405–417 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Popejoy, A. B. & Fullerton, S. M. Genomics is failing on diversity. Nature 538, 161–164 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Rosenberg, N. A. et al. Genome-wide association studies in diverse populations. Nat. Rev. Genet. 11, 356–366 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Schabath, M. B., Cress, D. & Munoz-Antonia, T. Racial and ethnic differences in the epidemiology and genomics of lung cancer. Cancer Control 23, 338–346 (2016).

    PubMed 
    Article 

    Google Scholar
     

  • Asimit, J. L., Hatzikotoulas, K., McCarthy, M., Morris, A. P. & Zeggini, E. Trans-ethnic study design approaches for fine-mapping. Eur. J. Hum. Genet. 24, 1330–1336 (2016).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Conti, D. V. et al. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat. Genet. 53, 65–75 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Magi, R. et al. Trans-ethnic meta-regression of genome-wide association studies accounting for ancestry increases power for discovery and improves fine-mapping resolution. Hum. Mol. Genet. 26, 3639–3650 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Li, Y. R. & Keating, B. J. Trans-ethnic genome-wide association studies: advantages and challenges of mapping in diverse populations. Genome Med. 6, 91 (2014).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Morris, A. P. Transethnic meta-analysis of genomewide association studies. Genet. Epidemiol. 35, 809–822 (2011).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Marigorta, U. M. & Navarro, A. High trans-ethnic replicability of GWAS results implies common causal variants. PLoS Genet. 9, e1003566 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wang, J. et al. Genetic predisposition to lung cancer: comprehensive literature integration, meta-analysis, and multiple evidence assessment of candidate-gene association studies. Sci. Rep. 7, 8371 (2017).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Bossé, Y. et al. Transcriptome-wide association study reveals candidate causal genes for lung cancer. Int. J. Cancer. 146, 1862–1878 (2020).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Kanwal, M., Ding, X. J. & Cao, Y. Familial risk for lung cancer. Oncol. Lett. 13, 535–542 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Rashkin, S. R. et al. Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts. Nat. Commun. 11, 4423 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Jiang, X. et al. Shared heritability and functional enrichment across six solid cancers. Nat. Commun. 10, 431 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • McKay, J. D. et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat. Genet. 49, 1126–1132 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Li, Y. et al. Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population. Carcinogenesis 39, 336–346 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Li, Y. et al. Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development. Oncotarget 10, 1760–1774 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Ji, X. et al. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk. Nat. Commun. 9, 3221 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Ji, X. et al. Protein-altering germline mutations implicate novel genes related to lung cancer development. Nat. Commun. 11, 2220 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Amos, C. I. et al. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiol. Biomarkers Prev. 26, 126–135 (2017).

    PubMed 
    Article 

    Google Scholar
     

  • Byun, J. et al. Genome-wide association study of familial lung cancer. Carcinogenesis 39, 1135–1140 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Lan, Q. et al. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia. Nat. Genet. 44, 1330–1335 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kachuri, L. et al. Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci. Carcinogenesis 37, 96–105 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Zanetti, K. A. et al. Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population. Lung Cancer 98, 33–42 (2016).

    PubMed 
    Article 

    Google Scholar
     

  • Wang, Y. et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat. Genet. 46, 736–741 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Truong, T. et al. Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J. Natl Cancer Inst. 102, 959–971 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Zuber, V. et al. Pleiotropic analysis of lung cancer and blood triglycerides. J. Natl Cancer. Inst. 108, djw167 (2016).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Watza, D. et al. COPD-dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk. Int. J. Cancer 147, 747–756 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Dai, J. et al. Identification of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations. Lancet Respir. Med. 7, 881–891 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • van Rooij, F. J. A. et al. Genome-wide trans-ethnic meta-analysis identifies seven genetic loci influencing erythrocyte traits and a role for RBPMS in erythropoiesis. Am. J. Hum. Genet. 100, 51–63 (2017).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Li, Y. et al. FastPop: a rapid principal component derived method to infer intercontinental ancestry using genetic data. BMC Bioinformatics 17, 122 (2016).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wang, X. Firth logistic regression for rare variant association tests. Front. Genet. 5, 187 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, C., Blackwell, T., Boehnke, M., Scott, L. J. & Go, T. D. I. Recommended joint and meta-analysis strategies for case-control association testing of single low-count variants. Genet. Epidemiol. 37, 539–550 (2013).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Dey, R. et al. Robust meta-analysis of biobank-based genome-wide association studies with unbalanced binary phenotypes. Genet. Epidemiol. 43, 462–476 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Han, B. & Eskin, E. Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am. J. Hum. Genet. 88, 586–598 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Han, B. & Eskin, E. Interpreting meta-analyses of genome-wide association studies. PLoS Genet. 8, e1002555 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Bhattacharjee, S. et al. A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits. Am. J. Hum. Genet. 90, 821–835 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Igl, B. W., Konig, I. R. & Ziegler, A. What do we mean by ‘replication’ and ‘validation’ in genome-wide association studies? Hum. Hered. 67, 66–68 (2009).

    PubMed 
    Article 

    Google Scholar
     

  • Spitz, M. R. et al. Role of selected genetic variants in lung cancer risk in African Americans. J. Thorac. Oncol. 8, 391–397 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Machiela, M. J. & Chanock, S. J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Buniello, A. et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–d1012 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Schumacher, F. R. et al. Genome-wide association study of colorectal cancer identifies six new susceptibility loci. Nat. Commun. 6, 7138 (2015).

    PubMed 
    Article 

    Google Scholar
     

  • Doyle, G. A. et al. In vitro and ex vivo analysis of CHRNA3 and CHRNA5 haplotype expression. PLoS ONE 6, e23373 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Tanner, J. A. et al. Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism. Pharmacogenet. Genomics 28, 7–16 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kang, E. Y. et al. Meta-analysis identifies gene-by-environment interactions as demonstrated in a study of 4,965 mice. PLoS Genet. 10, e1004022 (2014).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Pena-Chilet, M. et al. Genetic variants in PARP1 (rs3219090) and IRF4 (rs12203592) genes associated with melanoma susceptibility in a Spanish population. BMC Cancer 13, 160 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Chen, M. H. et al. Trans-ethnic and ancestry-specific blood-cell genetics in 746,667 individuals from 5 global populations. Cell 182, 1198–1213 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Vuckovic, D. et al. The polygenic and monogenic basis of blood traits and diseases. Cell 182, 1214–1231 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Astle, W. J. et al. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 167, 1415–1429 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Liyanage, U. E. et al. Combined analysis of keratinocyte cancers identifies novel genome-wide loci. Hum. Mol. Genet. 28, 3148–3160 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Asgari, M. M. et al. Identification of susceptibility loci for cutaneous squamous cell carcinoma. J. Invest. Dermatol. 136, 930–937 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Chahal, H. S. et al. Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma. Nat. Commun. 7, 12048 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Liu, M. et al. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use. Nat. Genet. 51, 237–244 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Kichaev, G. et al. Leveraging polygenic functional enrichment to improve GWAS power. Am. J. Hum. Genet. 104, 65–75 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Yang, J. et al. Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits. Nat. Genet. 44, 369–375 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Landi, M. T. et al. A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma. Am. J. Hum. Genet. 85, 679–691 (2009).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • McKay, J. D. et al. Lung cancer susceptibility locus at 5p15.33. Nat. Genet. 40, 1404–1406 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Hung, R. J. et al. Lung cancer risk in never-smokers of European descent is associated with genetic variation in the 5p15.33 TERT-CLPTM1Ll region. J. Thorac. Oncol. 14, 1360–1369 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Shiraishi, K. et al. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat. Genet. 44, 900–903 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Hu, Z. et al. A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat. Genet. 43, 792–796 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Hsiung, C. A. et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet. 6, e1001051 (2010).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Schaid, D. J., Chen, W. & Larson, N. B. From genome-wide associations to candidate causal variants by statistical fine-mapping. Nat. Rev. Genet. 19, 491–504 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Cannon, M. E. et al. Trans-ancestry Fine mapping and molecular assays identify regulatory variants at the ANGPTL8 HDL-C GWAS. Locus. G3 7, 3217–3227 (2017).

    CAS 
    PubMed 

    Google Scholar
     

  • Li, X. et al. Dynamic incorporation of multiple in silico functional annotations empowers rare variant association analysis of large whole-genome sequencing studies at scale. Nat. Genet. 52, 969–983 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Sun, R. et al. Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer. Genet. Epidemiol. 45, 99–114 (2021).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • Li, X. et al. A multi-dimensional integrative scoring framework for predicting functional variants in the human genome. Am. J. Hum. Genet. 109, 446–456 (2022).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Elman, J. S. et al. Identification of FUBP1 as a long tail cancer driver and widespread regulator of tumor suppressor and oncogene alternative splicing. Cell Rep. 28, 3435–3449 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Singer, S. et al. Coordinated expression of stathmin family members by far upstream sequence element-binding protein-1 increases motility in non-small cell lung cancer. Cancer Res. 69, 2234–2243 (2009).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155–1165 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Praetorius, C. et al. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 155, 1022–1033 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Do, T. N., Ucisik-Akkaya, E., Davis, C. F., Morrison, B. A. & Dorak, M. T. An intronic polymorphism of IRF4 gene influences gene transcription in vitro and shows a risk association with childhood acute lymphoblastic leukemia in males. Biochim. Biophys. Acta 1802, 292–300 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Zhang, T. et al. Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes. Genome Res. 28, 1621–1635 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Visser, M., Palstra, R. J. & Kayser, M. Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter. Hum. Mol. Genet. 24, 2649–2661 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Xia, J. et al. Bacteria-to-Human protein networks reveal origins of endogenous DNA damage. Cell 176, 127–143 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Liu, Y. et al. Rare deleterious germline variants and risk of lung cancer. NPJ Precis. Oncol. 5, 12 (2021).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Gomperts, B. N. et al. Evolving concepts in lung carcinogenesis. Semin. Respir. Crit. Care Med. 32, 32–43 (2011).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Miller, Y. E. Pathogenesis of lung cancer: 100 year report. Am. J. Respir. Cell Mol. Biol. 33, 216–223 (2005).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Landi, M. T. et al. Environment And Genetics in Lung cancer Etiology (EAGLE) study: an integrative population-based case-control study of lung cancer. BMC Public Health 8, 203 (2008).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Mitchell, K. A. et al. Relationship between West African ancestry with lung cancer risk and survival in African Americans. Cancer Causes Control 30, 1259–1268 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wigginton, J. E., Cutler, D. J. & Abecasis, G. R. A note on exact tests of Hardy–Weinberg equilibrium. Am. J. Hum. Genet. 76, 887–893 (2005).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Graffelman, J. & Moreno, V. The mid p-value in exact tests for Hardy–Weinberg equilibrium. Stat. Appl. Genet. Mol. Biol. 12, 433–448 (2013).

    PubMed 
    Article 

    Google Scholar
     

  • Rafnar, T. et al. Variants associating with uterine leiomyoma highlight genetic background shared by various cancers and hormone-related traits. Nat. Commun. 9, 3636 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • Genomes Project, C. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article 
    CAS 

    Google Scholar
     

  • Hormozdiari, F. et al. Colocalization of GWAS and eQTL signals detects target genes. Am. J. Hum. Genet. 99, 1245–1260 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Wallace, C. Eliciting priors and relaxing the single causal variant assumption in colocalisation analyses. PLoS Genet. 16, e1008720 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • Livak, K. J. & Schmittgen, T. D. Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 25, 402–408 (2001).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • Read more here: Source link