Genome-wide association studies: inherent limitations and future challenges

Abstract

Genome-wide association studies (GWAS) have achieved great success in identifying genetic variants related to complex human diseases such as cancer and have provided valuable insights into their genetic architecture. Recently, GWAS is quite the fashion in China. However, there are issues related to its nature. Enormous work needs to be done in the post-GWAS era. Deep sequencing followed by functional studies will be needed to elucidate the underpinning biological mechanisms and further translate GWAS findings into medical practice. Along with pharmacogenomics, the success of GWAS in identifying genetic risk factors and genetic differences in drug response has been gradually enabling personalized medicine. In this article, we used hepatocellular carcinoma (HCC) as an example to demonstrate some of the inherent limitations and summarized future challenges of GWAS.

Keywords

genome-wide association studies (GWAS) / genetic variant / cancer / limitation / challenge

References

[1] Long J, Zheng W, Xiang YB, Lose FA, Thompson DJ, Tomlinson I, Yu H, Wentzensen N, Lambrechts D, Dörk T, Dubrowinskaja N, Goodman MT, Salvesen HB, Fasching PA, Scott RJ, Delahanty R, Zheng Y, O’Mara TA, Healey CS, Hodgson SV, Risch H, Yang HP, Amant F, Turmanov N, Schwake A, Lurie G, Trovik J, Beckmann MW, Ashton KA, Ji BT, Bao PP, Howarth K, Lu L, Lissowska J, Coenegrachts L, Kaidarova D, Dürst M, Thompson PJ, Krakstad C, Ekici AB, Otton G, Shi J, Zhang B, Gorman M, Brinton LA, Coosemans A, Matsuno RK, Halle MK, Hein A, Proietto A, Cai H, Lu W, Dunning A, Easton DF, Gao YT, Cai Q, Spurdle AB, Shu XO. Genome-wide association study identifies a possible susceptibility locus for endometrial cancer. Cancer Epidemiol Biomarkers Prev2012; 21(6): 980-987

[2] Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, Ma F, Huang W, Yu L, Yue W, Wang Z, Li P, Zhang Y, Liang R, Wei Z, Cui Y, Xie W, Cai M, Yu X, Yuan Y, Xia X, Zhang X, Yang H, Qiu W, Yang J, Gong F, Chen M, Shen H, Lin D, Zeng YX, He F, Zhou G. Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet2010; 42(9): 755-758

[3] Chan KY, Wong CM, Kwan JS, Lee JM, Cheung KW, Yuen MF, Lai CL, Poon RT, Sham PC, Ng IO. Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection. PLoS ONE2011; 6(12): e28798

[4] Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, Yuan JM, Zheng W, Dawsey SM, Dong LM, Lee MP, Ding T, Qiao YL, Gao YT, Koh WP, Xiang YB, Tang ZZ, Fan JH, Wang C, Wheeler W, Gail MH, Yeager M, Yuenger J, Hutchinson A, Jacobs KB, Giffen CA, Burdett L, Fraumeni JF Jr, Tucker MA, Chow WH, Goldstein AM, Chanock SJ, Taylor PR. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet2010; 42(9): 764-767

[5] Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, Li JM, Kong GQ, Qi H, Cui J, Zhang LQ, Yang JZ, Li JL, Li XC, Ren JL, Liu ZC, Gao WJ, Yuan L, Wei W, Zhang YR, Wang WP, Sheyhidin I, Li F, Chen BP, Ren SW, Liu B, Li D, Ku JW, Fan ZM, Zhou SL, Guo ZG, Zhao XK, Liu N, Ai YH, Shen FF, Cui WY, Song S, Guo T, Huang J, Yuan C, Huang J, Wu Y, Yue WB, Feng CW, Li HL, Wang Y, Tian JY, Lu Y, Yuan Y, Zhu WL, Liu M, Fu WJ, Yang X, Wang HJ, Han SL, Chen J, Han M, Wang HY, Zhang P, Li XM, Dong JC, Xing GL, Wang R, Guo M, Chang ZW, Liu HL, Guo L, Yuan ZQ, Liu H, Lu Q, Yang LQ, Zhu FG, Yang XF, Feng XS, Wang Z, Li Y, Gao SG, Qige Q, Bai LT, Yang WJ, Lei GY, Shen ZY, Chen LQ, Li EM, Xu LY, Wu ZY, Cao WK, Wang JP, Bao ZQ, Chen JL, Ding GC, Zhuang X, Zhou YF, Zheng HF, Zhang Z, Zuo XB, Dong ZM, Fan DM, He X, Wang J, Zhou Q, Zhang QX, Jiao XY, Lian SY, Ji AF, Lu XM, Wang JS, Chang FB, Lu CD, Chen ZG, Miao JJ, Fan ZL, Lin RB, Liu TJ, Wei JC, Kong QP, Lan Y, Fan YJ, Gao FS, Wang TY, Xie D, Chen SQ, Yang WC, Hong JY, Wang L, Qiu SL, Cai ZM, Zhang XJ. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet2010; 42(9): 759-763

[6] Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y, Liu Z, Zhan Q, Liu Y, Yu D, Zhai K, Chang J, Qiao Y, Jin G, Liu Z, Shen Y, Guo C, Fu J, Miao X, Tan W, Shen H, Ke Y, Zeng Y, Wu T, Lin D. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet2011; 43(7): 679-684

[7] Shi Y, Hu Z, Wu C, Dai J, Li H, Dong J, Wang M, Miao X, Zhou Y, Lu F, Zhang H, Hu L, Jiang Y, Li Z, Chu M, Ma H, Chen J, Jin G, Tan W, Wu T, Zhang Z, Lin D, Shen H. A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1. Nat Genet2011; 43(12): 1215-1218

[8] Bei JX, Li Y, Jia WH, Feng BJ, Zhou G, Chen LZ, Feng QS, Low HQ, Zhang H, He F, Tai ES, Kang T, Liu ET, Liu J, Zeng YX. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat Genet2010; 42(7): 599-603

[9] Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, Yang L, Dai J, Hu L, Tan W, Li Z, Deng Q, Wang J, Wu W, Jin G, Jiang Y, Yu D, Zhou G, Chen H, Guan P, Chen Y, Shu Y, Xu L, Liu X, Liu L, Xu P, Han B, Bai C, Zhao Y, Zhang H, Yan Y, Ma H, Chen J, Chu M, Lu F, Zhang Z, Chen F, Wang X, Jin L, Lu J, Zhou B, Lu D, Wu T, Lin D, Shen H. A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat Genet2011; 43(8): 792-796

[10] Wu C, Miao X, Huang L, Che X, Jiang G, Yu D, Yang X, Cao G, Hu Z, Zhou Y, Zuo C, Wang C, Zhang X, Zhou Y, Yu X, Dai W, Li Z, Shen H, Liu L, Chen Y, Zhang S, Wang X, Zhai K, Chang J, Liu Y, Sun M, Cao W, Gao J, Ma Y, Zheng X, Cheung ST, Jia Y, Xu J, Tan W, Zhao P, Wu T, Wang C, Lin D. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet2012; 44(1): 62-66

[11] Milestone in Anhui. Nat Genet2011; 43(7): 613

[12] Amos CI, Wu X, Broderick P, Gorlov IP, Gu J, Eisen T, Dong Q, Zhang Q, Gu X, Vijayakrishnan J, Sullivan K, Matakidou A, Wang Y, Mills G, Doheny K, Tsai YY, Chen WV, Shete S, Spitz MR, Houlston RS. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet2008; 40(5): 616-622

[13] Hung RJ, McKay JD, Gaborieau V, Boffetta P, Hashibe M, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chen C, Goodman G, Field JK, Liloglou T, Xinarianos G, Cassidy A, McLaughlin J, Liu G, Narod S, Krokan HE, Skorpen F, Elvestad MB, Hveem K, Vatten L, Linseisen J, Clavel-Chapelon F, Vineis P, Bueno-de-Mesquita HB, Lund E, Martinez C, Bingham S, Rasmuson T, Hainaut P, Riboli E, Ahrens W, Benhamou S, Lagiou P, Trichopoulos D, Holcátová I, Merletti F, Kjaerheim K, Agudo A, Macfarlane G, Talamini R, Simonato L, Lowry R, Conway DI, Znaor A, Healy C, Zelenika D, Boland A, Delepine M, Foglio M, Lechner D, Matsuda F, Blanche H, Gut I, Heath S, Lathrop M, Brennan P. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature2008; 452(7187): 633-637

[14] Chung CC, Chanock SJ. Current status of genome-wide association studies in cancer. Hum Genet2011; 130(1): 59-78

[15] Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, Cho JH, Guttmacher AE, Kong A, Kruglyak L, Mardis E, Rotimi CN, Slatkin M, Valle D, Whittemore AS, Boehnke M, Clark AG, Eichler EE, Gibson G, Haines JL, Mackay TF, McCarroll SA, Visscher PM. Finding the missing heritability of complex diseases. Nature2009; 461(7265): 747-753

[16] Lango Allen H, Estrada K, Lettre G, Berndt S I, Weedon M N, Rivadeneira F, Willer C J, Jackson A U, Vedantam S, Raychaudhuri S, Ferreira T, Wood A R, Weyant R J, Segre A V, Speliotes E K, Wheeler E, Soranzo N, Park J H, Yang J, Gudbjartsson D, Heard-Costa N L, Randall J C, Qi L, Vernon Smith A, Magi R, Pastinen T, Liang L, Heid I M, Luan J, Thorleifsson G, Winkler T W, Goddard M E, Sin Lo K, Palmer C, Workalemahu T, Aulchenko Y S, Johansson A, Zillikens M C, Feitosa M F, Esko T, Johnson T, Ketkar S, Kraft P, Mangino M, Prokopenko I, Absher D, Albrecht E, Ernst F, Glazer N L, Hayward C, Hottenga J J, Jacobs K B, Knowles J W, Kutalik Z, Monda K L, Polasek O, Preuss M, Rayner N W, Robertson N R, Steinthorsdottir V, Tyrer J P, Voight B F, Wiklund F, Xu J, Zhao J H, Nyholt D R, Pellikka N, Perola M, Perry J R, Surakka I, Tammesoo M L, Altmaier E L, Amin N, Aspelund T, Bhangale T, Boucher G, Chasman D I, Chen C, Coin L, Cooper M N, Dixon A L, Gibson Q, Grundberg E, Hao K, Juhani Junttila M, Kaplan L M, Kettunen J, Konig I R, Kwan T, Lawrence R W, Levinson D F, Lorentzon M, McKnight B, Morris A P, Muller M, Suh Ngwa J, Purcell S, Rafelt S, Salem RM, Salvi E, Sanna S, Shi J, Sovio U, Thompson J R, Turchin M C, Vandenput L, Verlaan D J, Vitart V, White C C, Ziegler A, Almgren P, Balmforth A J, Campbell H, Citterio L, De Grandi A, Dominiczak A, Duan J, Elliott P, Elosua R, Eriksson J G, Freimer N B, Geus E J, Glorioso N, Haiqing S, Hartikainen A L, Havulinna A S, Hicks A A, Hui J, Igl W, Illig T, Jula A, Kajantie E, Kilpelainen T O, Koiranen M, Kolcic I, Koskinen S, Kovacs P, Laitinen J, Liu J, Lokki M L, Marusic A, Maschio A, Meitinger T, Mulas A, Pare G, Parker A N, Peden J F, Petersmann A, Pichler I, Pietilainen K H, Pouta A, Ridderstrale M, Rotter J I, Sambrook J G, Sanders A R, Schmidt C O, Sinisalo J, Smit J H, Stringham H M, Bragi Walters G, Widen E, Wild S H, Willemsen G, Zagato L, Zgaga L, Zitting P, Alavere H, Farrall M, McArdle W L, Nelis M, Peters M J, Ripatti S, van Meurs J B, Aben K K, Ardlie K G, Beckmann J S, Beilby J P, Bergman R N, Bergmann S, Collins F S, Cusi D, den Heijer M, Eiriksdottir G, Gejman P V, Hall A S, Hamsten A, Huikuri H V, Iribarren C, Kahonen M, Kaprio J, Kathiresan S, Kiemeney L, Kocher T, Launer L J, Lehtimaki T, Melander O, Mosley T H, Jr., Musk A W, Nieminen M S, O'Donnell C J, Ohlsson C, Oostra B, Palmer L J, Raitakari O, Ridker P M, Rioux J D, Rissanen A, Rivolta C, Schunkert H, Shuldiner A R, Siscovick D S, Stumvoll M, Tonjes A, Tuomilehto J, van Ommen G J, Viikari J, Heath A C, Martin N G, Montgomery G W, Province M A, Kayser M, Arnold A M, Atwood L D, Boerwinkle E, Chanock S J, Deloukas P, Gieger C, Gronberg H, Hall P, Hattersley A T, Hengstenberg C, Hoffman W, Lathrop G M, Salomaa V, Schreiber S, Uda M, Waterworth D, Wright A F, Assimes T L, Barroso I, Hofman A, Mohlke K L, Boomsma D I, Caulfield M J, Cupples L A, Erdmann J, Fox C S, Gudnason V, Gyllensten U, Harris T B, Hayes R B, Jarvelin M R, Mooser V, Munroe P B, Ouwehand W H, Penninx B W, Pramstaller P P, Quertermous T, Rudan I, Samani N J, Spector T D, Volzke H, Watkins H, Wilson J F, Groop L C, Haritunians T, Hu F B, Kaplan R C, Metspalu A, North K E, Schlessinger D, Wareham N J, Hunter D J, O'Connell J R, Strachan D P, Wichmann H E, Borecki I B, van Duijn C M, Schadt E E, Thorsteinsdottir U, Peltonen L, Uitterlinden A G, Visscher P M, Chatterjee N, Loos R J, Boehnke M, McCarthy M I, Ingelsson E, Lindgren C M, Abecasis G R, Stefansson K, Frayling T M, Hirschhorn J N. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature2010; 467(7317): 832-838

[17] Miki D, Ochi H, Hayes CN, Aikata H, Chayama K. Hepatocellular carcinoma: towards personalized medicine. Cancer Sci2012; 103(5): 846-850

[18] Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology2008; 48(6): 2047-2063

[19] Han YF, Zhao J, Ma LY, Yin JH, Chang WJ, Zhang HW, Cao GW. Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma. World J Gastroenterol2011; 17(38): 4258-4270

[20] Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: epidemiological characteristics and disease burden. J Viral Hepat2009; 16(7): 453-463

[21] Yin J, Xie J, Liu S, Zhang H, Han L, Lu W, Shen Q, Xu G, Dong H, Shen J, Zhang J, Han J, Wang L, Liu Y, Wang F, Zhao J, Zhang Q, Ni W, Wang H, Cao G. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma. Am J Gastroenterol2011; 106(1): 81-92

[22] Xie JX, Zhao J, Yin JH, Zhang Q, Pu R, Lu WY, Zhang HW, Wang HY, Cao GW. Association of novel mutations and haplotypes in the preS region of hepatitis B virus with hepatocellular carcinoma. Front Med China2010; 4(4): 419-429

[23] Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst2009; 101(15): 1066-1082

[24] Chen L, Hu L, Li L, Liu Y, Tu QQ, Chang YX, Yan HX, Wu MC, Wang HY. Dysregulation of β-catenin by hepatitis B virus X protein in HBV-infected human hepatocellular carcinomas. Front Med China2010; 4(4): 399-411

[25] Yin J, Xie J, Zhang H, Shen Q, Han L, Lu W, Han Y, Li C, Ni W, Wang H, Cao G. Significant association of different preS mutations with hepatitis B-related cirrhosis or hepatocellular carcinoma. J Gastroenterol2010; 45(10): 1063-1071

[26] Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H, Koike K, Kamatani N, Kubo M, Nakamura Y, Matsuda K. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet2011; 43(5): 455-458

[27] Miki D, Ochi H, Hayes CN, Abe H, Yoshima T, Aikata H, Ikeda K, Kumada H, Toyota J, Morizono T, Tsunoda T, Kubo M, Nakamura Y, Kamatani N, Chayama K. Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nat Genet2011; 43(8): 797-800

[28] Clifford RJ, Zhang J, Meerzaman DM, Lyu MS, Hu Y, Cultraro CM, Finney RP, Kelley JM, Efroni S, Greenblum SI, Nguyen CV, Rowe WL, Sharma S, Wu G, Yan C, Zhang H, Chung YH, Kim JA, Park NH, Song IH, Buetow KH. Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma. Hepatology2010; 52(6): 2034-2043

[29] Galichon P, Hertig A, Rondeau E, Mesnard L. Warning: genome-wide association studies can be misleading. An example in hepatology. Hepatology2011; 53(4): 1408, author reply 1408-1409

[30] Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet2010; 11(12): 843-854

[31] Braun R, Buetow K. Pathways of distinction analysis: a new technique for multi-SNP analysis of GWAS data. PLoS Genet2011; 7(6): e1002101

[32] Ku CS, Loy EY, Pawitan Y, Chia KS. The pursuit of genome-wide association studies: where are we now? J Hum Genet2010; 55(4): 195-206

[33] Hudson T. Genome-sequencing anniversary. Genomics and clinical relevance. Science2011; 331(6017): 547

Acknowledgements

This work was supported by the National Outstanding Youth Fund from National Natural Scientific Foundation of China (81025015 to Guangwen Cao).

Conflict of interest No potential conflicts of interest were disclosed.

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2014 Higher Education Press and Springer-Verlag Berlin Heidelberg