Hard Work Ahead: Fine Mapping and Functional Follow-up of Susceptibility Alleles in Cancer GWAS

详细信息    查看全文

• 作者：Roelof Koster ; Stephen J. Chanock
• 关键词：Post ; genome ; wide association studies ; Fine mapping ; Large ; scale collaborative efforts ; In silico functional studies
• 刊名：Current Epidemiology Reports
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：2
• 期：3
• 页码：205-217
• 全文大小：1197KB
• 参考文献：Papers of particular interest, published recently, have been highlighted as: 鈥?Of importance 鈥⑩€?Of major importance1.Risch NJ. Searching for genetic determinants in the new millennium. Nature. 2000;405(6788):847鈥?6.PubMed CrossRef
  2.Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480(7375):99鈥?03. doi:10.鈥?038/鈥媙ature10630 .PubMed Central PubMed CrossRef
  3.Group NCCM. A comprehensive genetic linkage map of the human genome. NIH/CEPH Collaborative Mapping Group. Science. 1992;258(5079):67鈥?6.CrossRef
  4.Elston RC, Cordell HJ. Overview of model-free methods for linkage analysis. Adv Genet. 2001;42:135鈥?0.PubMed CrossRef
  5.Hussussian CJ, Struewing JP, Goldstein AM, Higgins PA, Ally DS, Sheahan MD, et al. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8(1):15鈥?1. doi:10.鈥?038/鈥媙g0994-15 .PubMed CrossRef
  6.Kamb A, Shattuck-Eidens D, Eeles R, Liu Q, Gruis NA, Ding W, et al. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet. 1994;8(1):23鈥?. doi:10.鈥?038/鈥媙g0994-22 .PubMed CrossRef
  7.Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233鈥?.PubMed CrossRef
  8.Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266(5182):66鈥?1.PubMed CrossRef
  9.Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995;378(6559):789鈥?2. doi:10.鈥?038/鈥?78789a0 .PubMed CrossRef
  10.Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990;250(4988):1684鈥?.PubMed CrossRef
  11.鈥?/div>Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302鈥?. doi:10.鈥?038/鈥媙ature12981 . This paper catalogs the more than 110 genes in which a highly penetrant mutation leads to one or more cancers and first reports on the substantial overlap between predisposition genes and somatic drivers of cancer.PubMed CrossRef
  12.Knudson Jr AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971;68(4):820鈥?.PubMed Central PubMed CrossRef
  13.Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996;273(5281):1516鈥?.PubMed CrossRef
  14.Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995;11(3):241鈥?. doi:10.鈥?038/鈥媙g1195-241 .PubMed CrossRef
  15.Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409(6822):860鈥?21. doi:10.鈥?038/鈥?5057062 .PubMed CrossRef
  16.Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science. 2001;291(5507):1304鈥?1. doi:10.鈥?126/鈥媠cience.鈥?058040291/鈥?507/鈥?304 .PubMed CrossRef
  17.International HapMap Consortium. The International HapMap Project. Nature. 2003;426(6968):789鈥?6. doi:10.鈥?038/鈥媙ature02168 nature02168 .CrossRef
  18.Durbin RM, Abecasis GR, Altshuler DL, Auton A, Brooks LD, Gibbs RA, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061鈥?3. doi:10.鈥?038/鈥媙ature09534 .PubMed CrossRef
  19.Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, et al. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007;449(7164):851鈥?1.PubMed CrossRef
  20.Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, et al. Genome-wide detection and characterization of positive selection in human populations. Nature. 2007;449(7164):913鈥?. doi:10.鈥?038/鈥媙ature06250 .PubMed Central PubMed CrossRef
  21.鈥?/div>Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422):56鈥?5. doi:10.鈥?038/鈥媙ature11632 . This paper describes an important reference data set for in silico fine-mapping.PubMed CrossRef
  22.Orr N, Chanock S. Common genetic variation and human disease. Adv Genet. 2008;62:1鈥?2. doi:10.鈥?016/鈥媠0065-2660(08)00601-9 .PubMed CrossRef
  23.Goldstein DB. The importance of synthetic associations will only be resolved empirically. PLoS Biol. 2011;9(1), e1001008. doi:10.鈥?371/鈥媕ournal.鈥媝bio.鈥?001008 .PubMed Central PubMed CrossRef
  24.Barrett JC, Cardon LR. Evaluating coverage of genome-wide association studies. Nat Genet. 2006;38(6):659鈥?2. doi:10.鈥?038/鈥媙g1801 .PubMed CrossRef
  25.Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661鈥?8. doi:10.鈥?038/鈥媙ature05911 .CrossRef
  26.Chanock SJ, Manolio T, Boehnke M, Boerwinkle E, Hunter DJ, Thomas G, et al. Replicating genotype-phenotype associations. Nature. 2007;447(7145):655鈥?0. doi:10.鈥?038/鈥?47655a .PubMed CrossRef
  27.Chanock SJ. Genome-wide association studies. In: Stewart BW, Wild CP, editors. World Cancer Report 2014. Lyon: International Agency for Research on Cancer, World Health Organization; 2014.
  28.Welter D, MacArthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42(Database issue):D1001鈥?. doi:10.鈥?093/鈥媙ar/鈥媑kt1229 .PubMed Central PubMed CrossRef
  29.Hindorff LA, Gillanders EM, Manolio TA. Genetic architecture of cancer and other complex diseases: lessons learned and future directions. Carcinogenesis. 2011;32(7):945鈥?4. doi:10.鈥?093/鈥媍arcin/鈥媌gr056 .PubMed Central PubMed CrossRef
  30.Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A. 2009;106(23):9362鈥?. doi:10.鈥?073/鈥媝nas.鈥?903103106 .PubMed Central PubMed CrossRef
  31.Freedman ML, Monteiro AN, Gayther SA, Coetzee GA, Risch A, Plass C, et al. Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet. 2011;43(6):513鈥?. doi:10.鈥?038/鈥媙g.鈥?40 .PubMed Central PubMed CrossRef
  32.Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363(2):166鈥?6. doi:10.鈥?056/鈥婲EJMra0905980 .PubMed CrossRef
  33.Savage SA, Mirabello L, Wang Z, Gastier-Foster JM, Gorlick R, Khanna C, et al. Genome-wide association study identifies two susceptibility loci for osteosarcoma. Nat Genet. 2013;45(7):799鈥?03. doi:10.鈥?038/鈥媙g.鈥?645 .PubMed Central PubMed CrossRef
  34.Maris JM, Mosse YP, Bradfield JP, Hou C, Monni S, Scott RH, et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N Engl J Med. 2008;358(24):2585鈥?3. doi:10.鈥?056/鈥婲EJMoa0708698 .PubMed Central PubMed CrossRef
  35.Postel-Vinay S, Veron AS, Tirode F, Pierron G, Reynaud S, Kovar H, et al. Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet. 2012;44(3):323鈥?. doi:10.鈥?038/鈥媙g.鈥?085 .PubMed CrossRef
  36.Chung CC, Magalhaes WC, Gonzalez-Bosquet J, Chanock SJ. Genome-wide association studies in cancer鈥攃urrent and future directions. Carcinogenesis. 2010;31(1):111鈥?0. doi:10.鈥?093/鈥媍arcin/鈥媌gp273 .PubMed Central PubMed CrossRef
  37.Kanetsky PA, Mitra N, Vardhanabhuti S, Li M, Vaughn DJ, Letrero R, et al. Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet. 2009;41(7):811鈥?. doi:10.鈥?038/鈥媙g.鈥?93 .PubMed Central PubMed CrossRef
  38.Rapley EA, Turnbull C, Al Olama AA, Dermitzakis ET, Linger R, Huddart RA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet. 2009;41(7):807鈥?0. doi:10.鈥?038/鈥媙g.鈥?94 .PubMed Central PubMed CrossRef
  39.Chung CC, Kanetsky PA, Wang Z, Hildebrandt MA, Koster R, Skotheim RI, et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet. 2013;45(6):680鈥?. doi:10.鈥?038/鈥媙g.鈥?634 .PubMed CrossRef
  40.Ruark E, Seal S, McDonald H, Zhang F, Elliot A, Lau K, et al. Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet. 2013;45(6):686鈥?. doi:10.鈥?038/鈥媙g.鈥?635 .PubMed CrossRef
  41.Chung CC, Chanock SJ. Current status of genome-wide association studies in cancer. Hum Genet. 2011;130(1):59鈥?8. doi:10.鈥?007/鈥媠00439-011-1030-9 .PubMed CrossRef
  42.Turnbull C, Rapley EA, Seal S, Pernet D, Renwick A, Hughes D, et al. Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer. Nat Genet. 2010;42(7):604鈥?. doi:10.鈥?038/鈥媙g.鈥?07 .PubMed Central PubMed CrossRef
  43.Kanetsky PA, Mitra N, Vardhanabhuti S, Vaughn DJ, Li M, Ciosek SL, et al. A second independent locus within DMRT1 is associated with testicular germ cell tumor susceptibility. Hum Mol Genet. 2011;20(15):3109鈥?7. doi:10.鈥?093/鈥媓mg/鈥媎dr207 .PubMed Central PubMed CrossRef
  44.鈥⑩€?/div>Diskin SJ, Capasso M, Schnepp RW, Cole KA, Attiyeh EF, Hou C, et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat Genet. 2012;44(10):1126鈥?0. doi:10.鈥?038/鈥媙g.鈥?387 . This manuscript describes the rare instance of susceptibility loci that are associated with more advanced disease and survival.
  45.鈥⑩€?/div>Wang K, Diskin SJ, Zhang H, Attiyeh EF, Winter C, Hou C, et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature. 2011;469(7329):216鈥?0. doi:10.鈥?038/鈥媙ature09609 . This manuscript describes the rare instance of susceptibility loci that are associated with more advanced disease and survival.
  46.Wu C, Li D, Jia W, Hu Z, Zhou Y, Yu D, et al. Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma. Nat Genet. 2013. doi:10.鈥?038/鈥媙g.鈥?638 .
  47.Barrdahl M, Canzian F, Lindstrom S, Shui I, Black A, Hoover RN, et al. Association of breast cancer risk loci with breast cancer survival. Int J Cancer. 2015. doi:10.鈥?002/鈥媔jc.鈥?9446 .PubMed
  48.Pirie A, Guo Q, Kraft P, Canisius S, Eccles DM, Rahman N, et al. Common germline polymorphisms associated with breast cancer specific survival. Breast Cancer Res : BCR. 2015;17(1):58. doi:10.鈥?186/鈥媠13058-015-0570-7 .PubMed Central PubMed CrossRef
  49.Guo Q, Schmidt MK, Kraft P, Canisius S, Chen C, Khan S et al. Identification of novel genetic markers of breast cancer survival. J Natl Cancer Inst. 2015;107(5). doi:10.鈥?093/鈥媕nci/鈥媎jv081 .
  50.Guenther CA, Tasic B, Luo L, Bedell MA, Kingsley DM. A molecular basis for classic blond hair color in Europeans. Nat Genet. 2014;46(7):748鈥?2. doi:10.鈥?038/鈥媙g.鈥?991 .PubMed CrossRef
  51.Miller CT, Beleza S, Pollen AA, Schluter D, Kittles RA, Shriver MD, et al. cis-Regulatory changes in Kit ligand expression and parallel evolution of pigmentation in sticklebacks and humans. Cell. 2007;131(6):1179鈥?9. doi:10.鈥?016/鈥媕.鈥媍ell.鈥?007.鈥?0.鈥?55 .PubMed Central PubMed CrossRef
  52.鈥⑩€?/div>Zeron-Medina J, Wang X, Repapi E, Campbell MR, Su D, Castro-Giner F, et al. A polymorphic p53 response element in KIT ligand influences cancer risk and has undergone natural selection. Cell. 2013;155(2):410鈥?2. doi:10.鈥?016/鈥媕.鈥媍ell.鈥?013.鈥?9.鈥?17 . This manuscript provides a compelling argument for the high frequency of a common variant that displays pleiotropy, associated with not only hair color but an early adult disease, testicular cancer.PubMed Central PubMed CrossRef
  53.Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007;39(5):638鈥?4. doi:10.鈥?038/鈥媙g2015 .PubMed Central PubMed CrossRef
  54.Al Olama AA, Kote-Jarai Z, Giles GG, Guy M, Morrison J, Severi G, et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet. 2009;41(10):1058鈥?0. doi:10.鈥?038/鈥媙g.鈥?52 .PubMed CrossRef
  55.Crowther-Swanepoel D, Broderick P, Di Bernardo MC, Dobbins SE, Torres M, Mansouri M, et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet. 2010;42(2):132鈥?. doi:10.鈥?038/鈥媙g.鈥?10 .PubMed CrossRef
  56.Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature. 2007;447(7148):1087鈥?3. doi:10.鈥?038/鈥媙ature05887 .PubMed Central PubMed CrossRef
  57.Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, et al. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet. 2007;39(5):631鈥?. doi:10.鈥?038/鈥媙g1999 .PubMed CrossRef
  58.Kiemeney LA, Thorlacius S, Sulem P, Geller F, Aben KK, Stacey SN, et al. Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet. 2008;40(11):1307鈥?2. doi:10.鈥?038/鈥媙g.鈥?29 .PubMed CrossRef
  59.Tomlinson I, Webb E, Carvajal-Carmona L, Broderick P, Kemp Z, Spain S, et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet. 2007;39(8):984鈥?. doi:10.鈥?038/鈥媙g2085 .PubMed CrossRef
  60.Zanke BW, Greenwood CM, Rangrej J, Kustra R, Tenesa A, Farrington SM, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet. 2007;39(8):989鈥?4. doi:10.鈥?038/鈥媙g2089 .PubMed CrossRef
  61.Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, et al. A common variant associated with prostate cancer in European and African populations. Nat Genet. 2006;38(6):652鈥?. doi:10.鈥?038/鈥媙g1808 .PubMed CrossRef
  62.Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet. 2007;39(5):645鈥?. doi:10.鈥?038/鈥媙g2022 .PubMed CrossRef
  63.Yeager M, Chatterjee N, Ciampa J, Jacobs KB, Gonzalez-Bosquet J, Hayes RB, et al. Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat Genet. 2009;41(10):1055鈥?. doi:10.鈥?038/鈥媙g.鈥?44 .PubMed Central PubMed CrossRef
  64.Sur IK, Hallikas O, Vaharautio A, Yan J, Turunen M, Enge M, et al. Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science. 2012;338(6112):1360鈥?. doi:10.鈥?126/鈥媠cience.鈥?228606 .PubMed CrossRef
  65.Pomerantz MM, Ahmadiyeh N, Jia L, Herman P, Verzi MP, Doddapaneni H, et al. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet. 2009;41(8):882鈥?. doi:10.鈥?038/鈥媙g.鈥?03 .PubMed Central PubMed CrossRef
  66.Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, et al. The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet. 2009;41(8):885鈥?0. doi:10.鈥?038/鈥媙g.鈥?06 .PubMed CrossRef
  67.Skibola CF, Bracci PM, Halperin E, Conde L, Craig DW, Agana L, et al. Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet. 2009;41(8):873鈥?. doi:10.鈥?038/鈥媙g.鈥?19 .PubMed Central PubMed CrossRef
  68.Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N, et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet. 2010;42(8):661鈥?. doi:10.鈥?038/鈥媙g.鈥?26 .PubMed Central PubMed CrossRef
  69.Wang SS, Menashe I, Cerhan JR, Cozen W, Severson RK, Davis S, et al. Variations in chromosomes 9 and 6p21.3 with risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2011;20(1):42鈥?. doi:10.鈥?158/鈥?055-9965.鈥婨PI-10-0638 .PubMed CrossRef
  70.Bei JX, Li Y, Jia WH, Feng BJ, Zhou G, Chen LZ, et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet. 2010;42(7):599鈥?03. doi:10.鈥?038/鈥媙g.鈥?01 .PubMed CrossRef
  71.Tse KP, Su WH, Chang KP, Tsang NM, Yu CJ, Tang P, et al. Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3. Am J Hum Genet. 2009;85(2):194鈥?03. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?009.鈥?7.鈥?07 .PubMed Central PubMed CrossRef
  72.Cerhan JR, Berndt SI, Vijai J, Ghesquieres H, McKay J, Wang SS, et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat Genet. 2014;46(11):1233鈥?. doi:10.鈥?038/鈥媙g.鈥?105 .PubMed Central PubMed CrossRef
  73.Vijai J, Wang Z, Berndt SI, Skibola CF, Slager SL, de Sanjose S, et al. A genome-wide association study of marginal zone lymphoma shows association to the HLA region. Nat Commun. 2015;6:5751. doi:10.鈥?038/鈥媙comms6751 .PubMed Central PubMed CrossRef
  74.Hsiung CA, Lan Q, Hong YC, Chen CJ, Hosgood HD, Chang IS et al. The 5p15.33 locus is associated with risk of lung adenocarcinoma in never-smoking females in Asia. PLoS Genet. 2010;6(8). doi:10.鈥?371/鈥媕ournal.鈥媝gen.鈥?001051 .
  75.Landi MT, Chatterjee N, Yu K, Goldin LR, Goldstein AM, Rotunno M, 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. 2009;85(5):679鈥?1. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?009.鈥?9.鈥?12 .PubMed Central PubMed CrossRef
  76.Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet. 2009;41(8):899鈥?04. doi:10.鈥?038/鈥媙g.鈥?07 .PubMed Central PubMed CrossRef
  77.Broderick P, Wang Y, Vijayakrishnan J, Matakidou A, Spitz MR, Eisen T, et al. Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer Res. 2009;69(16):6633鈥?1. doi:10.鈥?158/鈥?008-5472.鈥婥AN-09-0680 .PubMed Central PubMed CrossRef
  78.McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet. 2008;40(12):1404鈥?. doi:10.鈥?038/鈥媙g.鈥?54 .PubMed Central PubMed CrossRef
  79.Petersen GM, Amundadottir L, Fuchs CS, Kraft P, Stolzenberg-Solomon RZ, Jacobs KB, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42(3):224鈥?. doi:10.鈥?038/鈥媙g.鈥?22 .PubMed Central PubMed CrossRef
  80.Wang Y, Broderick P, Webb E, Wu X, Vijayakrishnan J, Matakidou A, et al. Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet. 2008;40(12):1407鈥?. doi:10.鈥?038/鈥媙g.鈥?73 .PubMed Central PubMed CrossRef
  81.Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978鈥?4. doi:10.鈥?038/鈥媙g.鈥?87 .PubMed Central PubMed CrossRef
  82.Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet. 2009;41(2):221鈥?. doi:10.鈥?038/鈥媙g.鈥?96 .PubMed CrossRef PubMed Central
  83.Wang Z, Zhu B, Zhang M, Parikh H, Jia J, Chung CC, et al. Imputation and subset based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Hum Mol Genet. 2014. doi:10.鈥?093/鈥媓mg/鈥媎du363 .
  84.Terrin L, Trentin L, Degan M, Corradini I, Bertorelle R, Carli P, et al. Telomerase expression in B-cell chronic lymphocytic leukemia predicts survival and delineates subgroups of patients with the same igVH mutation status and different outcome. Leukemia. 2007;21(5):965鈥?2. doi:10.鈥?038/鈥媠j.鈥媗eu.鈥?404607 .PubMed
  85.Calado RT, Regal JA, Hills M, Yewdell WT, Dalmazzo LF, Zago MA, et al. Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. Proc Natl Acad Sci U S A. 2009;106(4):1187鈥?2. doi:10.鈥?073/鈥媝nas.鈥?807057106 .PubMed Central PubMed CrossRef
  86.Calado RT, Regal JA, Kleiner DE, Schrump DS, Peterson NR, Pons V, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009;4(11), e7926. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?007926 .PubMed Central PubMed CrossRef
  87.Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352(14):1413鈥?4. doi:10.鈥?056/鈥婲EJMoa042980 .PubMed CrossRef
  88.Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci U S A. 2007;104(18):7552鈥?. doi:10.鈥?073/鈥媝nas.鈥?701009104 .PubMed Central PubMed CrossRef
  89.Mushiroda T, Wattanapokayakit S, Takahashi A, Nukiwa T, Kudoh S, Ogura T, et al. A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis. J Med Genet. 2008;45(10):654鈥?. doi:10.鈥?136/鈥媕mg.鈥?008.鈥?57356 .PubMed CrossRef
  90.Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317鈥?6. doi:10.鈥?056/鈥婲EJMoa066157 .PubMed CrossRef
  91.Stacey SN, Sulem P, Masson G, Gudjonsson SA, Thorleifsson G, Jakobsdottir M, et al. New common variants affecting susceptibility to basal cell carcinoma. Nat Genet. 2009;41(8):909鈥?4. doi:10.鈥?038/鈥媙g.鈥?12 .PubMed Central PubMed CrossRef
  92.Shea J, Agarwala V, Philippakis AA, Maguire J, Banks E, Depristo M, et al. Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction. Nat Genet. 2011;43(8):801鈥?. doi:10.鈥?038/鈥媙g.鈥?71 .PubMed Central PubMed CrossRef
  93.Li WQ, Pfeiffer RM, Hyland PL, Shi J, Gu F, Wang Z, et al. Genetic polymorphisms in the 9p21 region associated with risk of multiple cancers. Carcinogenesis. 2014;35(12):2698鈥?05. doi:10.鈥?093/鈥媍arcin/鈥媌gu203 .PubMed CrossRef
  94.Gu F, Pfeiffer RM, Bhattacharjee S, Han SS, Taylor PR, Berndt S, et al. Common genetic variants in the 9p21 region and their associations with multiple tumours. Br J Cancer. 2013;108(6):1378鈥?6. doi:10.鈥?038/鈥媌jc.鈥?013.鈥? .PubMed Central PubMed CrossRef
  95.Harismendy O, Notani D, Song X, Rahim NG, Tanasa B, Heintzman N, et al. 9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response. Nature. 2011;470(7333):264鈥?. doi:10.鈥?038/鈥媙ature09753 .PubMed Central PubMed CrossRef
  96.Yasuno K, Bilguvar K, Bijlenga P, Low SK, Krischek B, Auburger G, et al. Genome-wide association study of intracranial aneurysm identifies three new risk loci. Nat Genet. 2010;42(5):420鈥?. doi:10.鈥?038/鈥媙g.鈥?63 .PubMed Central PubMed CrossRef
  97.Hannou SA, Wouters K, Paumelle R, Staels B. Functional genomics of the CDKN2A/B locus in cardiovascular and metabolic disease: what have we learned from GWASs? Trends Endocrinol Metab TEM. 2015;26(4):176鈥?4. doi:10.鈥?016/鈥媕.鈥媡em.鈥?015.鈥?1.鈥?08 .PubMed CrossRef
  98.Garcia-Closas M, Hall P, Nevanlinna H, Pooley K, Morrison J, Richesson DA, et al. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics. PLoS Genet. 2008;4(4), e1000054. doi:10.鈥?371/鈥媕ournal.鈥媝gen.鈥?000054 .PubMed Central PubMed CrossRef
  99.Hustinx SR, Leoni LM, Yeo CJ, Brown PN, Goggins M, Kern SE, et al. Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion. Mod Pathol : Off J US Can Acad Pathol Inc. 2005;18(7):959鈥?3. doi:10.鈥?038/鈥媘odpathol.鈥?800377 .CrossRef
  100.Goldstein AM. Familial melanoma, pancreatic cancer and germline CDKN2A mutations. Hum Mutat. 2004;23(6):630. doi:10.鈥?002/鈥媓umu.鈥?247 .PubMed CrossRef
  101.Eeles RA, Olama AA, Benlloch S, Saunders EJ, Leongamornlert DA, Tymrakiewicz M, et al. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nat Genet. 2013;45(4):385鈥?1. doi:10.鈥?038/鈥媙g.鈥?560 .PubMed CrossRef
  102.Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, et al. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353鈥?1. doi:10.鈥?038/鈥媙g.鈥?563 .PubMed Central PubMed CrossRef
  103.Pharoah PD, Tsai YY, Ramus SJ, Phelan CM, Goode EL, Lawrenson K, et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat Genet. 2013;45(4):362鈥?0. doi:10.鈥?038/鈥媙g.鈥?564 .PubMed Central PubMed CrossRef
  104.鈥?/div>Wang Z, Jacobs KB, Yeager M, Hutchinson A, Sampson J, Chatterjee N, et al. Improved imputation of common and uncommon SNPs with a new reference set. Nat Genet. 2012;44(1):6鈥?. doi:10.鈥?038/鈥媙g.鈥?044 . This paper describes a reference data set of individuals from three cohorts who were genotyped on most commercial SNP microarrays, thus providing a standard for concordance and for in silico finemapping.CrossRef
  105.鈥?/div>Genome of the Netherlands. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat Genet. 2014. doi:10.鈥?038/鈥媙g.鈥?021 . This resource portrays the population genetics of a European nation and serves as a fine reference data set for in silico finemapping.
  106.鈥⑩€?/div>Wang Y, McKay JD, Rafnar T, Wang Z, Timofeeva MN, Broderick P, et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat Genet. 2014;46(7):736鈥?1. doi:10.鈥?038/鈥媙g.鈥?002 . Identified rare variants with large effect size using imputation and meta-analysis of large-scaled data sets.PubMed Central PubMed CrossRef
  107.Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet. 2014;46(10):1103鈥?. doi:10.鈥?038/鈥媙g.鈥?094 .PubMed Central PubMed CrossRef
  108.Cai Q, Zhang B, Sung H, Low SK, Kweon SS, Lu W, et al. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet. 2014;46(8):886鈥?0. doi:10.鈥?038/鈥媙g.鈥?041 .PubMed Central PubMed CrossRef
  109.Park JH, Wacholder S, Gail MH, Peters U, Jacobs KB, Chanock SJ, et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet. 2010;42(7):570鈥?. doi:10.鈥?038/鈥媙g.鈥?10 .PubMed CrossRef
  110.Chatterjee N, Wheeler B, Sampson J, Hartge P, Chanock SJ, Park JH. Projecting the performance of risk prediction based on polygenic analyses of genome-wide association studies. Nat Genet. 2013;45(4):400鈥?. doi:10.鈥?038/鈥媙g.鈥?579 .PubMed Central PubMed CrossRef
  111.Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet. 2010;11(12):843鈥?4. doi:10.鈥?038/鈥媙rg2884 .PubMed CrossRef
  112.Segre AV, Groop L, Mootha VK, Daly MJ, Altshuler D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 2010;6(8). doi:10.鈥?371/鈥媕ournal.鈥媝gen.鈥?001058 .
  113.Nam D, Kim J, Kim SY, Kim S. GSA-SNP: a general approach for gene set analysis of polymorphisms. Nucleic Acids Res. 2010;38(Web Server issue):W749鈥?4. doi:10.鈥?093/鈥媙ar/鈥媑kq428 .PubMed Central PubMed CrossRef
  114.Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet. 2009;41(3):324鈥?. doi:10.鈥?038/鈥媙g.鈥?18 .PubMed Central PubMed CrossRef
  115.Menashe I, Maeder D, Garcia-Closas M, Figueroa JD, Bhattacharjee S, Rotunno M, et al. Pathway analysis of breast cancer genome-wide association study highlights three pathways and one canonical signaling cascade. Cancer Res. 2010;70(11):4453鈥?. doi:10.鈥?158/鈥?008-5472.鈥婥AN-09-4502 .PubMed Central PubMed CrossRef
  116.Lee YH, Kim JH, Song GG. Genome-wide pathway analysis of breast cancer. Tumour Biol. 2014. doi:10.鈥?007/鈥媠13277-014-2027-5 .PubMed Central
  117.Koster R, Mitra N, D鈥橝ndrea K, Vardhanabhuti S, Chung CC, Wang Z, et al. Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors. Hum Mol Genet. 2014. doi:10.鈥?093/鈥媓mg/鈥媎du305 .
  118.Schoof N, Iles MM, Bishop DT, Newton-Bishop JA, Barrett JH. Pathway-based analysis of a melanoma genome-wide association study: analysis of genes related to tumour-immunosuppression. PLoS One. 2011;6(12), e29451. doi:10.鈥?371/鈥媕ournal.鈥媝one.鈥?029451 .PubMed Central PubMed CrossRef
  119.de Las Fuentes L, Yang W, Davila-Roman VG, Gu CC. Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets. Eur J Hum Genet. 2012. doi:10.鈥?038/鈥媏jhg.鈥?012.鈥?6 .
  120.Liu G, Jiang Y, Wang P, Feng R, Jiang N, Chen X, et al. Cell adhesion molecules contribute to Alzheimer鈥檚 disease: multiple pathway analyses of two genome-wide association studies. J Neurochem. 2012;120(1):190鈥?. doi:10.鈥?111/鈥媕.鈥?471-4159.鈥?011.鈥?7547.鈥媥 .PubMed CrossRef
  121.Consortium IMSG. Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. Am J Hum Genet. 2013. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?013.鈥?4.鈥?19 .
  122.Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, et al. Genome-wide association studies identify four ER negative-specific breast cancer risk loci. Nat Genet. 2013;45(4):392鈥?. doi:10.鈥?038/鈥媙g.鈥?561 .PubMed Central PubMed CrossRef
  123.Berndt S, Wang Z, Yeager M, Alavanja MC, Albanes D, Amundadottir L, et al. Two susceptibility loci identified for prostate cancer aggressiveness. Nat Commun. 2015;6:6889.PubMed CrossRef
  124.Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA. http://鈥媏vs.鈥媑s.鈥媤ashington.鈥媏du/鈥婨VS/鈥?/span> .
  125.Tennessen JA, Bigham AW, O鈥機onnor TD, Fu W, Kenny EE, Gravel S, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012;337(6090):64鈥?. doi:10.鈥?126/鈥媠cience.鈥?219240 .PubMed Central PubMed CrossRef
  126.Parikh H, Deng Z, Yeager M, Boland J, Matthews C, Jia J, et al. A comprehensive resequence analysis of the KLK15-KLK3-KLK2 locus on chromosome 19q13.33. Hum Genet. 2010;127(1):91鈥?. doi:10.鈥?007/鈥媠00439-009-0751-5 .PubMed Central PubMed CrossRef
  127.Yeager M, Xiao N, Hayes RB, Bouffard P, Desany B, Burdett L, et al. Comprehensive resequence analysis of a 136 kb region of human chromosome 8q24 associated with prostate and colon cancers. Hum Genet. 2008;124(2):161鈥?0. doi:10.鈥?007/鈥媠00439-008-0535-3 .PubMed Central PubMed CrossRef
  128.Yeager M, Deng Z, Boland J, Matthews C, Bacior J, Lonsberry V, et al. Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer. Hum Genet. 2009;126(6):743鈥?0. doi:10.鈥?007/鈥媠00439-009-0723-9 .PubMed Central PubMed CrossRef
  129.Meyer KB, O鈥橰eilly M, Michailidou K, Carlebur S, Edwards SL, French JD, et al. Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1. Am J Hum Genet. 2013;93(6):1046鈥?0. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?013.鈥?0.鈥?26 .PubMed Central PubMed CrossRef
  130.Eeles RA, Kote-Jarai Z, Al Olama AA, Giles GG, Guy M, Severi G, et al. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet. 2009;41(10):1116鈥?1. doi:10.鈥?038/鈥媙g.鈥?50 .PubMed Central PubMed CrossRef
  131.Winkler CA, Nelson GW, Smith MW. Admixture mapping comes of age. Annu Rev Genomics Hum Genet. 2010;11:65鈥?9. doi:10.鈥?146/鈥媋nnurev-genom-082509-141523 .PubMed CrossRef
  132.Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337(6099):1190鈥?. doi:10.鈥?126/鈥媠cience.鈥?222794 .PubMed Central PubMed CrossRef
  133.Jones FC, Grabherr MG, Chan YF, Russell P, Mauceli E, Johnson J, et al. The genomic basis of adaptive evolution in threespine sticklebacks. Nature. 2012;484(7392):55鈥?1. doi:10.鈥?038/鈥媙ature10944 .PubMed Central PubMed CrossRef
  134.Grossman SR, Andersen KG, Shlyakhter I, Tabrizi S, Winnicki S, Yen A, et al. Identifying recent adaptations in large-scale genomic data. Cell. 2013;152(4):703鈥?3. doi:10.鈥?016/鈥媕.鈥媍ell.鈥?013.鈥?1.鈥?35 .PubMed Central PubMed CrossRef
  135.Fraser HB. Gene expression drives local adaptation in humans. Genome Res. 2013;23(7):1089鈥?6. doi:10.鈥?101/鈥媑r.鈥?52710.鈥?12 .PubMed Central PubMed CrossRef
  136.Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menendez-Rodriguez P, et al. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium. Hum Mol Genet. 2014;23(22):6096鈥?11. doi:10.鈥?093/鈥媓mg/鈥媎du311 .PubMed Central PubMed CrossRef
  137.Nicolae DL, Gamazon E, Zhang W, Duan S, Dolan ME, Cox NJ. Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet. 2010;6(4), e1000888. doi:10.鈥?371/鈥媕ournal.鈥媝gen.鈥?000888 .PubMed Central PubMed CrossRef
  138.Fehrmann RS, Jansen RC, Veldink JH, Westra HJ, Arends D, Bonder MJ, et al. Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet. 2011;7(8), e1002197. doi:10.鈥?371/鈥媕ournal.鈥媝gen.鈥?002197 .PubMed Central PubMed CrossRef
  139.Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009;10(3):184鈥?4. doi:10.鈥?038/鈥媙rg2537 .PubMed CrossRef
  140.鈥?/div>Kim HS, Minna JD, White MA. GWAS meets TCGA to illuminate mechanisms of cancer predisposition. Cell. 2013;152(3):387鈥?. doi:10.鈥?016/鈥媕.鈥媍ell.鈥?013.鈥?1.鈥?27 . This paper illustrates the value of combining multiple datasets to map and investigate the biological underpinnings of common cancer susceptibility alleles.PubMed CrossRef
  141.Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061鈥?. doi:10.鈥?038/鈥媙ature07385 .CrossRef
  142.Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, Miller CB, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470鈥?0. doi:10.鈥?056/鈥婲EJMoa0808253 .PubMed Central PubMed CrossRef
  143.Consortium G. The Genotype-Tissue Expression (GTEx) project. Nat Genet. 2013;45(6):580鈥?. doi:10.鈥?038/鈥媙g.鈥?653 .CrossRef
  144.Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28(10):1045鈥?. doi:10.鈥?038/鈥媙bt1010-1045 .PubMed Central PubMed CrossRef
  145.Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317鈥?0. doi:10.鈥?038/鈥媙ature14248 .PubMed CrossRef
  146.鈥?/div>Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57鈥?4. doi:10.鈥?038/鈥媙ature11247 . A landmark paper describing the ENCODE project, which provides a survey of functional elements in the genome in reference cell lines.CrossRef
  147.Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Database issue):D930鈥?. doi:10.鈥?093/鈥媙ar/鈥媑kr917 .PubMed Central PubMed CrossRef
  148.Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790鈥?. doi:10.鈥?101/鈥媑r.鈥?37323.鈥?12 .PubMed Central PubMed CrossRef
  149.鈥⑩€?/div>Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45(2):164鈥?1. doi:10.鈥?038/鈥媙g.鈥?521 . Illustrates the clever use of bioinformatics resources leading to unexpected findings, namely the 'creation' of a new gene by a dinucleotide variant.PubMed Central PubMed CrossRef
  150.O鈥橞rien TR, Prokunina-Olsson L, Donnelly RP. IFN-lambda4: the paradoxical new member of the interferon lambda family. J interferon Cytokine Res : Off J Int Soc Interferon Cytokine Res. 2014;34(11):829鈥?8. doi:10.鈥?089/鈥媕ir.鈥?013.鈥?136 .CrossRef
  151.Edwards SL, Beesley J, French JD, Dunning AM. Beyond GWASs: illuminating the dark road from association to function. Am J Hum Genet. 2013;93(5):779鈥?7. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?013.鈥?0.鈥?12 .PubMed Central PubMed CrossRef
  152.Ward LD, Kellis M. Interpreting noncoding genetic variation in complex traits and human disease. Nat Biotechnol. 2012;30(11):1095鈥?06. doi:10.鈥?038/鈥媙bt.鈥?422 .PubMed Central PubMed CrossRef
  153.French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, et al. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. Am J Hum Genet. 2013;92(4):489鈥?03. doi:10.鈥?016/鈥媕.鈥媋jhg.鈥?013.鈥?1.鈥?02 .PubMed Central PubMed CrossRef
  154.Wu X, Ye Y, Kiemeney LA, Sulem P, Rafnar T, Matullo G, et al. Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat Genet. 2009;41(9):991鈥?. doi:10.鈥?038/鈥媙g.鈥?21 .PubMed Central PubMed CrossRef
  155.鈥?/div>Kohaar I, Porter-Gill P, Lenz P, Fu YP, Mumy A, Tang W, et al. Genetic variant as a selection marker for anti-prostate stem cell antigen immunotherapy of bladder cancer. J Natl Cancer Inst. 2013;105(1):69鈥?3. doi:10.鈥?093/鈥媕nci/鈥媎js458 . This paper describes the biological basis for understanding a bladder cancer susceptibility allele, which, in turn, could be a suitable target for clinical intervention.PubMed Central PubMed CrossRef
  156.Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. Emerging landscape of oncogenic signatures across human cancers. Nat Genet. 2013;45(10):1127鈥?3. doi:10.鈥?038/鈥媙g.鈥?762 .PubMed Central PubMed CrossRef
  157.Mardis ER. A decade鈥檚 perspective on DNA sequencing technology. Nature. 2011;470(7333):198鈥?03. doi:10.鈥?038/鈥媙ature09796 .PubMed CrossRef
  158.Bertolotto C, Lesueur F, Giuliano S, Strub T, de Lichy M, Bille K, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011;480(7375):94鈥?. doi:10.鈥?038/鈥媙ature10539 .PubMed CrossRef
  159.Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet. 2014;46(5):482鈥?. doi:10.鈥?038/鈥媙g.鈥?941 .PubMed Central PubMed CrossRef
  160.Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478鈥?1. doi:10.鈥?038/鈥媙g.鈥?947 .PubMed Central PubMed CrossRef
  161.Bolton KL, Chenevix-Trench G, Goh C, Sadetzki S, Ramus SJ, Karlan BY, et al. Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA : J Am Med Assoc. 2012;307(4):382鈥?0. doi:10.鈥?001/鈥媕ama.鈥?012.鈥?0 .CrossRef
  162.Pharoah PD, Antoniou AC, Easton DF, Ponder BA. Polygenes, risk prediction, and targeted prevention of breast cancer. N Engl J Med. 2008;358(26):2796鈥?03. doi:10.鈥?056/鈥婲EJMsa0708739 .PubMed CrossRef
  163.Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793鈥?. doi:10.鈥?056/鈥婲EJMp1500523 .PubMed CrossRef
  
• 作者单位：Roelof Koster (1)
  Stephen J. Chanock (1)
  
  1. Division of Cancer Epidemiology & Genetics, National Cancer Institute, Room 7E412, 9609 Medical Center Drive, Rockville, MD, 20850, USA
  
• 刊物类别：Epidemiology;
• 刊物主题：Epidemiology;
• 出版者：Springer International Publishing
• ISSN：2196-2995

文摘

Genome-wide association studies (GWAS) in cancer have successfully identified over 450 regions that harbor susceptibility alleles with small effects contributing to the risk of one or more cancers. Less than 10 % of the regions identified thus far are common to more than one cancer, but it is these regions which display pleiotropy that are especially informative and provide new opportunities to gain insights into common mechanisms of carcinogenesis. Since the GWAS age has been notable for scalability, large-scale consortia have successfully combined many studies to identify novel regions associated with risk for cancer. In fact, for common cancers, a substantial fraction of markers for common alleles have been identified, and additional studies of the cumulative 鈥減olygenic鈥?effect of large scans further suggest that many additional alleles remain to be characterized. The emerging catalog of common variants, which represents a fraction of the underlying genetic architecture of cancer susceptibility, already constitutes a set for common cancers that could be used in stratification and public health measures. On the other hand, the discovery of many regions is occurring at a rate that exceeds our capacity to understand the underlying biology contributing to each risk allele. Nearly all susceptibility regions harbor one or more variants that point towards changes in the regulation of key genes and pathways and not protein coding changes resulting in 鈥渄rivers鈥?of somatic alterations. Further investigation of each region depends upon the sequence of fine mapping (e.g., identification of correlated variants) using in silico functional tools to nominate the most promising variants for detailed laboratory follow-up studies. Each region has to be interrogated individually, taking into account the unique features of each genomic locale in order to understand the biological underpinnings of the susceptibility variants. Building a comprehensive catalog of susceptibility alleles, across a spectrum of frequencies and effect sizes, and functional annotation of these should be instrumental in revealing new cancer biology and eventually used in precision prevention. Keywords Post-genome-wide association studies Fine mapping Large-scale collaborative efforts In silico functional studies