The genome-wide association study (GWAS) is an effective method to detect single-nucleotide polymorphisms (SNPs) of multiple individual genes based on linkage disequilibrium (LD). GWAS examines genotypes and distinguishing gene characteristics that are exhibited in diseases. In the past few decades, more and more literature has reported the results of applying GWAS to study tumors. Although many pleiotropic loci associated with complex phenotypes have been identified by GWAS, the biological functions of many genetic variation loci remain unclear, and the genetic mechanisms of most complex phenotypes cannot be systematically explained. In this article, we will review the new findings of several tumor types, and categorize the new sites and mechanisms that have recently been discovered. We linked the mechanisms of action of various tumors and searched for links to related gene expression pathways. We found that susceptible sites can be divided into hub genes and peripheral genes; the two interact to link gene expression in a variety of diseases.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Arnold CD, Gerlach D et al (2013) Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339(6123):1074–1077. https://doi.org/10.1126/science.1232542
Baxter JS, Leavy OC et al (2018) Capture Hi-C identifies putative target genes at 33 breast cancer risk loci. Nat Commun 9(1):1028. https://doi.org/10.1038/s41467-018-03411-9
Boyle EA, Li YI et al (2017) An expanded view of complex traits: from polygenic to omnigenic. Cell 169(7):1177–1186. https://doi.org/10.1016/j.cell.2017.05.038
Cerhan JR, Berndt SI et al (2014) Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet 46(11):1233–1238. https://doi.org/10.1038/ng.3105
Cha PC, Zembutsu H et al (2012) A genome-wide association study identifies SNP in DCC is associated with gallbladder cancer in the Japanese population. J Hum Genet 57(4):235–237. https://doi.org/10.1038/jhg.2012.9
Chang J, Zhong R et al (2018) Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma. Nat Genet 50(3):338–343. https://doi.org/10.1038/s41588-018-0045-8
Cheng TH, Thompson DJ et al (2016) Five endometrial cancer risk loci identified through genome-wide association analysis. Nat Genet 48(6):667–674. https://doi.org/10.1038/ng.3562
Childs EJ, Mocci E et al (2015) Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat Genet 47(8):911–916. https://doi.org/10.1038/ng.3341
Davies RW, Flint J et al (2016) Rapid genotype imputation from sequence without reference panels. Nat Genet 48(8):965–969. https://doi.org/10.1038/ng.3594
Ferreira MA, Gamazon ER et al (2019) Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nat Commun 10(1):1741. https://doi.org/10.1038/s41467-018-08053-5
Gamazon ER, Wheeler HE et al (2015) A gene-based association method for mapping traits using reference transcriptome data. Nat Genet 47(9):1091–1098. https://doi.org/10.1038/ng.3367
Green ED, Watson JD et al (2015) Human genome project: twenty-five years of big biology. Nature 526(7571):29–31. https://doi.org/10.1038/526029a
Han JY, Shin ES et al (2013) A genome-wide association study for irinotecan-related severe toxicities in patients with advanced non-small-cell lung cancer. Pharmacogenomics J 13(5):417–422. https://doi.org/10.1038/tpj.2012.24
Hoffmann TJ, Passarelli MN et al (2017) Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer. Nat Commun 8:14248. https://doi.org/10.1038/ncomms14248
Hu N, Wang Z et al (2016) Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours. Gut 65(10):1611–1618. https://doi.org/10.1136/gutjnl-2015-309340
Huyghe JR, Bien SA et al (2019) Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet 51(1):76–87. https://doi.org/10.1038/s41588-018-0286-6
International HapMap C (2003) The international HapMap project. Nature 426(6968):789–796. https://doi.org/10.1038/nature02168
Kelemen LE, Lawrenson K et al (2015) Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47(8):888–897. https://doi.org/10.1038/ng.3336
Klein AP, Wolpin BM et al (2018) Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun 9(1):556. https://doi.org/10.1038/s41467-018-02942-5
Li Y, Sheu CC et al (2010) Genetic variants and risk of lung cancer in never smokers: a genome-wide association study. Lancet Oncol 11(4):321–330. https://doi.org/10.1016/S1470-2045(10)70042-5
Li WQ, Pfeiffer RM et al (2014) Genetic polymorphisms in the 9p21 region associated with risk of multiple cancers. Carcinogenesis 35(12):2698–2705. https://doi.org/10.1093/carcin/bgu203
Liao X, Yu L et al (2018) Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways associated with TP53 expression status in HBV-related hepatocellular carcinoma. Cancer Manag Res 10:953–967. https://doi.org/10.2147/CMAR.S163209
Lin X, Yan C et al (2017) Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Sci 108(2):250–255. https://doi.org/10.1111/cas.13130
Liu S, Liu Y et al (2017) Systematic identification of regulatory variants associated with cancer risk. Genome Biol 18(1):194. https://doi.org/10.1186/s13059-017-1322-z
Matsuse M, Takahashi M et al (2011) The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population. J Med Genet 48(9):645–648. https://doi.org/10.1136/jmedgenet-2011-100063
Matsuura K, Sawai H et al (2017) Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 152(6):1383–1394. https://doi.org/10.1053/j.gastro.2017.01.041
McKay JD, Hung RJ et al (2017) Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet 49(7):1126–1132. https://doi.org/10.1038/ng.3892
Mhatre S, Wang Z et al (2017) Common genetic variation and risk of gallbladder cancer in India: a case-control genome-wide association study. Lancet Oncol 18(4):535–544. https://doi.org/10.1016/S1470-2045(17)30167-5
Michailidou K, Beesley J et al (2015) Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer. Nat Genet 47(4):373–380. https://doi.org/10.1038/ng.3242
Mitchell JS, Li N et al (2016) Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun 7:12050. https://doi.org/10.1038/ncomms12050
Morton LM, Sampson JN et al (2017) Genome-wide association study to identify susceptibility loci that modify radiation-related risk for breast cancer after childhood cancer. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx058
Nicod J, Davies RW et al (2016) Genome-wide association of multiple complex traits in outbred mice by ultra-low-coverage sequencing. Nat Genet 48(8):912–918. https://doi.org/10.1038/ng.3595
Northcott PA, Buchhalter I et al (2017) The whole-genome landscape of medulloblastoma subtypes. Nature 547(7663):311–317. https://doi.org/10.1038/nature22973
Oei L, Estrada K et al (2014) Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone 59:20–27
O'Mara TA, Glubb DM et al (2019) Genome-wide association studies of endometrial cancer: latest developments and future directions. Cancer Epidemiol Biomark Prev 28(7):1095–1102. https://doi.org/10.1158/1055-9965.EPI-18-1031
Ponder BA (2001) Cancer genetics. Nature 411(6835):336–341. https://doi.org/10.1038/35077207
Rogounovitch TI, Bychkov A et al (2015) The common genetic variant rs944289 on chromosome 14q13.3 associates with risk of both malignant and benign thyroid tumors in the Japanese population. Thyroid 25(3):333–340. https://doi.org/10.1089/thy.2014.0431
Shu L, Chan KHK et al (2017) Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States. PLoS Genet 13(9):e1007040. https://doi.org/10.1371/journal.pgen.1007040
Sud A, Thomsen H et al (2017) Genome-wide association study of classical Hodgkin lymphoma identifies key regulators of disease susceptibility. Nat Commun 8(1):1892. https://doi.org/10.1038/s41467-017-00320-1
Sun Q, Wang Y et al (2019) Association of expression quantitative trait loci for long noncoding RNAs with lung cancer risk in Asians. Mol Carcinog. https://doi.org/10.1002/mc.23013
Tang J, Xu Z et al (2019a) Transcriptional regulation in model organisms: recent progress and clinical implications. Open Biol 9(11):190183. https://doi.org/10.1098/rsob.190183
Tang X, Huang Y et al (2019b) The single-cell sequencing: new developments and medical applications. Cell Biosci 9:53. https://doi.org/10.1186/s13578-019-0314-y
Tang Z, Li D et al (2019c) The cancer exosomes: clinical implications, applications and challenges. Int J Cancer. https://doi.org/10.1002/ijc.32762
Tanikawa C, Kamatani Y et al (2018) Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21. Cancer Sci 109(12):4015–4024. https://doi.org/10.1111/cas.13815
Visconti A, Duffy DL et al (2018) Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure. Nat Commun 9(1):1684. https://doi.org/10.1038/s41467-018-04086-y
Voskarides K (2018) Combination of 247 genome-wide association studies reveals high cancer risk as a result of evolutionary adaptation. Mol Biol Evol 35(2):473–485. https://doi.org/10.1093/molbev/msx305
Wang YL, Feng SH et al (2013) Confirmation of papillary thyroid cancer susceptibility loci identified by genome-wide association studies of chromosomes 14q13, 9q22, 2q35 and 8p12 in a Chinese population. J Med Genet 50(10):689–695. https://doi.org/10.1136/jmedgenet-2013-101687
Wang G, Yin H et al (2019) Characterization and identification of long non-coding RNAs based on feature relationship. Bioinformatics 35(17):2949–2956. https://doi.org/10.1093/bioinformatics/btz008
Wei Q, Yu D et al (2014) Genome-wide association study identifies three susceptibility loci for laryngeal squamous cell carcinoma in the Chinese population. Nat Genet 46(10):1110–1114. https://doi.org/10.1038/ng.3090
Wellcome Trust Case Control C (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678. https://doi.org/10.1038/nature05911
Wu C, Wang Z et al (2014) Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations. Nat Genet 46(9):1001–1006. https://doi.org/10.1038/ng.3064
Wu L, Shi W et al (2018) A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nat Genet 50(7):968–978. https://doi.org/10.1038/s41588-018-0132-x
Xiao Q, Chen L et al (2018) A rare CHD5 haplotype and its interactions with environmental factors predicting hepatocellular carcinoma risk. BMC Cancer 18(1):658. https://doi.org/10.1186/s12885-018-4551-y
Yang TL, Chen XD et al (2008) Genome-wide copy-number-variation study identified a susceptibility gene, UGT2B17, for osteoporosis. Am J Hum Genet 83(6):663–674. https://doi.org/10.1016/j.ajhg.2008.10.006
Yang CK, Yu TD et al (2017) Genome-wide association study of MKI67 expression and its clinical implications in HBV-related hepatocellular carcinoma in Southern China. Cell Physiol Biochem 42(4):1342–1357. https://doi.org/10.1159/000478963
Zhang XJ, Huang W et al (2009) Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21. Nat Genet 41(2):205–210. https://doi.org/10.1038/ng.310
Zhang B, Chen MY et al (2018) A large-scale, exome-wide association study of Han Chinese women identifies three novel loci predisposing to breast cancer. Can Res 78(11):3087–3097. https://doi.org/10.1158/0008-5472.CAN-17-1721
Zhao L, Wei Y et al (2016) Association study between genome-wide significant variants of vitamin B12 metabolism and gastric cancer in a han Chinese population. IUBMB Life 68(4):303–310. https://doi.org/10.1002/iub.1485
Zhu X, Kong Q et al (2018a) The single-nucleotide polymorphisms in CHD5 affect the prognosis of patients with hepatocellular carcinoma. Oncotarget 9(17):13222–13230. https://doi.org/10.18632/oncotarget.23812
Zhu Z, Zheng Z et al (2018b) Causal associations between risk factors and common diseases inferred from GWAS summary data. Nat Commun 9(1):224. https://doi.org/10.1038/s41467-017-02317-2
Zhu X, Luo H et al (2019) Transcriptome analysis reveals an important candidate gene involved in both nodal metastasis and prognosis in lung adenocarcinoma. Cell Biosci 9:92. https://doi.org/10.1186/s13578-019-0356-1
We would like to thank Alan Larson (firstname.lastname@example.org), Department of Family Medicine and Public Health, School of Medicine, University of California San Diego, and Biaoru Li (email@example.com), Cancer Center, Medical College of Georgia in Augusta University for English language revision.
This work was supported partly by the Southern Marine Science and Engineering Guangdong Laboratory Zhanjiang (ZJW-2019-07); National Natural Science Foundation of China (81541153); Guangdong Provincial Science and Technology Department (2016A050503046, 2015A050502048 and 2016B030309002); The Public Service Platform of South China Sea for R&D Marine Biomedicine Resources (GDMUK201808), Zhanjiang Science and Technology Plan (2017A06012); Guangdong Province Natural Science Foundation (2018A030310155); and “Group-type” Special Supporting Project for Educational Talents in Universities (4SG19057G). The funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Communicated by Stefan Hohmann.
About this article
Cite this article
Liang, B., Ding, H., Huang, L. et al. GWAS in cancer: progress and challenges. Mol Genet Genomics 295, 537–561 (2020). https://doi.org/10.1007/s00438-020-01647-z
- Susceptible gene