Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Wang, Z.; Zhu, B.; Zhang, M.; Parikh, H.; Jia, J.; Chung, C.C.; Sampson, J.N.; Hoskins, J.W.; Hutchinson, A.; Burdette, L.; Ibrahim, A.; Hautman, C.; Raj, P.S.; Abnet, C.C.; Adjei, A.A.; Ahlbom, A.; Albanes, D.; Allen, N.E.; Ambrosone, C.B.; Aldrich, M.; Amiano, P.; Amos, C.; Andersson, U.; Andriole, G.; Andrulis, I.L.; Arici, C.; Arslan, A.A.; Austin, M.A.; Baris, D.; Barkauskas, D.A.; Bassig, B.A.; Beane Freeman, L.E.; Berg, C.D.; Berndt, S.I.; Bertazzi, P.A.; Biritwum, R.B.; Black, A.; Blot, W.; Boeing, H.; Boffetta, P.; Bolton, K.; Boutron Ruault, M.; Bracci, P.M.; Brennan, P.; Brinton, L.A.; Brotzman, M.; Bueno de Mesquita, H.B.; Buring, J.E.; Butler, M.A.; Cai, Q.; Cancel Tassin, G.; Canzian, F.; Cao, G.; Caporaso, N.E.; Carrato, A.; Carreon, T.; Carta, A.; Chang, G.; Chang, I.; Chang Claude, J.; Che, X.; Chen, C.; Chen, C.; Chen, C.; Chen, C.; Chen, K.; Chen, Y.; Chokkalingam, A.P.; Chu, L.W.; Clavel Chapelon, F.; Colditz, G.A.; Colt, J.S.; Conti, D.; Cook, M.B.; Cortessis, V.K.; Crawford, E.D.; Cussenot, O.; Davis, F.G.; De Vivo, I.; Deng, X.; Ding, T.; Dinney, C.P.; Di Stefano, A.L.; Diver, W.R.; Duell, E.J.; Elena, J.W.; Fan, J.; Feigelson, H.S.; Feychting, M.; Figueroa, J.D.; Flanagan, A.M.; Fraumeni, J.F.; Freedman, N.D.; Fridley, B.L.; Fuchs, C.S.; Gago Dominguez, M.; Gallinger, S.; Gao, Y.; Gapstur, S.M.; Garcia Closas, M.; Garcia Closas, R.; Gastier Foster, J.M.; Gaziano, J.M.; Gerhard, D.S.; Giffen, C.A.; Giles, G.G.; Gillanders, E.M.; Giovannucci, E.L.; Goggins, M.; Gokgoz, N.; Goldstein, A.M.; Gonzalez, C.; Gorlick, R.; Greene, M.H.; Gross, M.; Grossman, H.B.; Grubb, R.; Gu, J.; Guan, P.; Haiman, C.A.; Hallmans, G.; Hankinson, S.E.; Harris, C.C.; Hartge, P.; Hattinger, C.; Hayes, R.B.; He, Q.; Helman, L.; Henderson, B.E.; Henriksson, R.; Hoffman Bolton, J.; Hohensee, C.; Holly, E.A.; Hong, Y.; Hoover, R.N.; Hosgood, H.D.; Hsiao, C.; Hsing, A.W.; Hsiung, C.A.; Hu, N.; Hu, W.; Hu, Z.; Huang, M.; Hunter, D.J.; Inskip, P.D.; Ito, H.; Jacobs, E.J.; Jacobs, K.B.; Jenab, M.; Ji, B.; Johansen, C.; Johansson, M.; Johnson, A.; Kaaks, R.; Kamat, A.M.; Kamineni, A.; Karagas, M.; Khanna, C.; Khaw, K.; Kim, C.; Kim, I.; Kim, Y.H.; Kim, Y.; Kim, Y.T.; Kang, C.H.; Jung, Y.J.; Kitahara, C.M.; Klein, A.P.; Klein, R.; Kogevinas, M.; Koh, W.; Kohno, T.; Kolonel, L.N.; Kooperberg, C.; Kratz, C.P.; Krogh, V.; Kunitoh, H.; Kurtz, R.C.; Kurucu, N.; Lan, Q.; Lathrop, M.; Lau, C.C.; Lecanda, F.; Lee, K.; Lee, M.P.; Le Marchand, L.; Lerner, S.P.; Li, D.; Liao, L.M.; Lim, W.; Lin, D.; Lin, J.; Lindstrom, S.; Linet, M.S.; Lissowska, J.; Liu, J.; Ljungberg, B.; Lloreta, J.; Lu, D.; Ma, J.; Malats, N.; Mannisto, S.; Marina, N.; Mastrangelo, G.; Matsuo, K.; Mcglynn, K.A.; McKean Cowdin, R.; Mcneill, L.H.; Mcwilliams, R.R.; Melin, B.S.; Meltzer, P.S.; Mensah, J.E.; Miao, X.; Michaud, D.S.; Mondul, A.M.; Moore, L.E.; Muir, K.; Niwa, S.; Olson, S.H.; Orr, N.; Panico, S.; Park, J.Y.; Patel, A.V.; Patino Garcia, A.; Pavanello, S.; Peeters, P.H.M.; Peplonska, B.; Peters, U.; Petersen, G.M.; Picci, P.; Pike, M.C.; Porru, S.; Prescott, J.; Pu, X.; Purdue, M.P.; Qiao, Y.; Rajaraman, P.; Riboli, E.; Risch, H.A.; Rodabough, R.J.; Rothman, N.; Ruder, A.M.; Ryu, J.; Sanson, M.; Schned, A.; Schumacher, F.R.; Schwartz, A.G.; Schwartz, K.L.; Schwenn, M.; Scotlandi, K.; Seow, A.; Serra, C.; Serra, M.; Sesso, H.D.; Severi, G.; Shen, H.; Shen, M.; Shete, S.; Shiraishi, K.; Shu, X.; Siddiq, A.; Sierrasesumaga, L.; Sierri, S.; Loon Sihoe, A.D.; Silverman, D.T.; Simon, M.; Southey, M.C.; Spector, L.; Spitz, M.; Stampfer, M.; Stattin, P.; Stern, M.C.; Stevens, V.L.; Stolzenberg Solomon, R.Z.; Stram, D.O.; Strom, S.S.; Su, W.; Sund, M.; Sung, S.W.; Swerdlow, A.; Tan, W.; Tanaka, H.; Tang, W.; Tang, Z.; Tardon, A.; Tay, E.; Taylor, P.R.; Tettey, Y.; Thomas, D.M.; Tirabosco, R.; Tjonneland, A.; Tobias, G.S.; Toro, J.R.; Travis, R.C.; Trichopoulos, D.; Troisi, R.; Truelove, A.; Tsai, Y.; Tucker, M.A.; Tumino, R.; Van Den Berg, D.; Van Den Eeden, S.K.; Vermeulen, R.; Vineis, P.; Visvanathan, K.; Vogel, U.; Wang, C.; Wang, C.; Wang, J.; Wang, S.S.; Weiderpass, E.; Weinstein, S.J.; Wentzensen, N.; Wheeler, W.; White, E.; Wiencke, J.K.; Wolk, A.; Wolpin, B.M.; Wong, M.P.; Wrensch, M.; Wu, C.; Wu, T.; Wu, X.; Wu, Y.; Wunder, J.S.; Xiang, Y.; Xu, J.; Yang, H.P.; Yang, P.; Yatabe, Y.; Ye, Y.; Yeboah, E.D.; Yin, Z.; Ying, C.; Yu, C.; Yu, K.; Yuan, J.; Zanetti, K.A.; Zeleniuch Jacquotte, A.; Zheng, W.; Zhou, B.; Mirabello, L.; Savage, S.A.; Kraft, P.; Chanock, S.J.; Yeager, M.; Landi, M.T.; Shi, J.; Chatterjee, N.; Amundadottir, L.T.

doi:10.1093/hmg/ddu363

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33 / Z. Wang, B. Zhu, M. Zhang, H. Parikh, J. Jia, C.C. Chung, J.N. Sampson, J.W. Hoskins, A. Hutchinson, L. Burdette, A. Ibrahim, C. Hautman, P.S. Raj, C.C. Abnet, A.A. Adjei, A. Ahlbom, D. Albanes, N.E. Allen, C.B. Ambrosone, M. Aldrich, P. Amiano, C. Amos, U. Andersson, G. Andriole, I.L. Andrulis, C. Arici, A.A. Arslan, M.A. Austin, D. Baris, D.A. Barkauskas, B.A. Bassig, L.E. Beane Freeman, C.D. Berg, S.I. Berndt, P.A. Bertazzi, R.B. Biritwum, A. Black, W. Blot, H. Boeing, P. Boffetta, K. Bolton, M. Boutron Ruault, P.M. Bracci, P. Brennan, L.A. Brinton, M. Brotzman, H.B. Bueno de Mesquita, J.E. Buring, M.A. Butler, Q. Cai, G. Cancel Tassin, F. Canzian, G. Cao, N.E. Caporaso, A. Carrato, T. Carreon, A. Carta, G. Chang, I. Chang, J. Chang Claude, X. Che, C. Chen, C. Chen, C. Chen, C. Chen, K. Chen, Y. Chen, A.P. Chokkalingam, L.W. Chu, F. Clavel Chapelon, G.A. Colditz, J.S. Colt, D. Conti, M.B. Cook, V.K. Cortessis, E.D. Crawford, O. Cussenot, F.G. Davis, I. De Vivo, X. Deng, T. Ding, C.P. Dinney, A.L. Di Stefano, W.R. Diver, E.J. Duell, J.W. Elena, J. Fan, H.S. Feigelson, M. Feychting, J.D. Figueroa, A.M. Flanagan, J.F. Fraumeni, N.D. Freedman, B.L. Fridley, C.S. Fuchs, M. Gago Dominguez, S. Gallinger, Y. Gao, S.M. Gapstur, M. Garcia Closas, R. Garcia Closas, J.M. Gastier Foster, J.M. Gaziano, D.S. Gerhard, C.A. Giffen, G.G. Giles, E.M. Gillanders, E.L. Giovannucci, M. Goggins, N. Gokgoz, A.M. Goldstein, C. Gonzalez, R. Gorlick, M.H. Greene, M. Gross, H.B. Grossman, R. Grubb, J. Gu, P. Guan, C.A. Haiman, G. Hallmans, S.E. Hankinson, C.C. Harris, P. Hartge, C. Hattinger, R.B. Hayes, Q. He, L. Helman, B.E. Henderson, R. Henriksson, J. Hoffman Bolton, C. Hohensee, E.A. Holly, Y. Hong, R.N. Hoover, H.D. Hosgood, C. Hsiao, A.W. Hsing, C.A. Hsiung, N. Hu, W. Hu, Z. Hu, M. Huang, D.J. Hunter, P.D. Inskip, H. Ito, E.J. Jacobs, K.B. Jacobs, M. Jenab, B. Ji, C. Johansen, M. Johansson, A. Johnson, R. Kaaks, A.M. Kamat, A. Kamineni, M. Karagas, C. Khanna, K. Khaw, C. Kim, I. Kim, Y.H. Kim, Y. Kim, Y.T. Kim, C.H. Kang, Y.J. Jung, C.M. Kitahara, A.P. Klein, R. Klein, M. Kogevinas, W. Koh, T. Kohno, L.N. Kolonel, C. Kooperberg, C.P. Kratz, V. Krogh, H. Kunitoh, R.C. Kurtz, N. Kurucu, Q. Lan, M. Lathrop, C.C. Lau, F. Lecanda, K. Lee, M.P. Lee, L. Le Marchand, S.P. Lerner, D. Li, L.M. Liao, W. Lim, D. Lin, J. Lin, S. Lindstrom, M.S. Linet, J. Lissowska, J. Liu, B. Ljungberg, J. Lloreta, D. Lu, J. Ma, N. Malats, S. Mannisto, N. Marina, G. Mastrangelo, K. Matsuo, K.A. Mcglynn, R. McKean Cowdin, L.H. Mcneill, R.R. Mcwilliams, B.S. Melin, P.S. Meltzer, J.E. Mensah, X. Miao, D.S. Michaud, A.M. Mondul, L.E. Moore, K. Muir, S. Niwa, S.H. Olson, N. Orr, S. Panico, J.Y. Park, A.V. Patel, A. Patino Garcia, S. Pavanello, P.H.M. Peeters, B. Peplonska, U. Peters, G.M. Petersen, P. Picci, M.C. Pike, S. Porru, J. Prescott, X. Pu, M.P. Purdue, Y. Qiao, P. Rajaraman, E. Riboli, H.A. Risch, R.J. Rodabough, N. Rothman, A.M. Ruder, J. Ryu, M. Sanson, A. Schned, F.R. Schumacher, A.G. Schwartz, K.L. Schwartz, M. Schwenn, K. Scotlandi, A. Seow, C. Serra, M. Serra, H.D. Sesso, G. Severi, H. Shen, M. Shen, S. Shete, K. Shiraishi, X. Shu, A. Siddiq, L. Sierrasesumaga, S. Sierri, A.D. Loon Sihoe, D.T. Silverman, M. Simon, M.C. Southey, L. Spector, M. Spitz, M. Stampfer, P. Stattin, M.C. Stern, V.L. Stevens, R.Z. Stolzenberg Solomon, D.O. Stram, S.S. Strom, W. Su, M. Sund, S.W. Sung, A. Swerdlow, W. Tan, H. Tanaka, W. Tang, Z. Tang, A. Tardon, E. Tay, P.R. Taylor, Y. Tettey, D.M. Thomas, R. Tirabosco, A. Tjonneland, G.S. Tobias, J.R. Toro, R.C. Travis, D. Trichopoulos, R. Troisi, A. Truelove, Y. Tsai, M.A. Tucker, R. Tumino, D. Van Den Berg, S.K. Van Den Eeden, R. Vermeulen, P. Vineis, K. Visvanathan, U. Vogel, C. Wang, C. Wang, J. Wang, S.S. Wang, E. Weiderpass, S.J. Weinstein, N. Wentzensen, W. Wheeler, E. White, J.K. Wiencke, A. Wolk, B.M. Wolpin, M.P. Wong, M. Wrensch, C. Wu, T. Wu, X. Wu, Y. Wu, J.S. Wunder, Y. Xiang, J. Xu, H.P. Yang, P. Yang, Y. Yatabe, Y. Ye, E.D. Yeboah, Z. Yin, C. Ying, C. Yu, K. Yu, J. Yuan, K.A. Zanetti, A. Zeleniuch Jacquotte, W. Zheng, B. Zhou, L. Mirabello, S.A. Savage, P. Kraft, S.J. Chanock, M. Yeager, M.T. Landi, J. Shi, N. Chatterjee, L.T. Amundadottir. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 23:24(2014 Dec 15), pp. 6616-6633. [10.1093/hmg/ddu363]

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Z. Wang;B. Zhu;M. Zhang;H. Parikh;J. Jia;C. C. Chung;J. N. Sampson;J. W. Hoskins;A. Hutchinson;L. Burdette;A. Ibrahim;C. Hautman;P. S. Raj;C. C. Abnet;A. A. Adjei;A. Ahlbom;D. Albanes;N. E. Allen;C. B. Ambrosone;M. Aldrich;P. Amiano;C. Amos;U. Andersson;G. Andriole;I. L. Andrulis;C. Arici;A. A. Arslan;M. A. Austin;D. Baris;D. A. Barkauskas;B. A. Bassig;L. E. Beane Freeman;C. D. Berg;S. I. Berndt;P.A. Bertazzi;R. B. Biritwum;A. Black;W. Blot;H. Boeing;P. Boffetta;K. Bolton;M. Boutron Ruault;P. M. Bracci;P. Brennan;L. A. Brinton;M. Brotzman;H. B. Bueno de Mesquita;J. E. Buring;M. A. Butler;Q. Cai;G. Cancel Tassin;F. Canzian;G. Cao;N. E. Caporaso;A. Carrato;T. Carreon;A. Carta;G. Chang;I. Chang;J. Chang Claude;X. Che;C. Chen;C. Chen;C. Chen;C. Chen;K. Chen;Y. Chen;A. P. Chokkalingam;L. W. Chu;F. Clavel Chapelon;G. A. Colditz;J. S. Colt;D. Conti;M. B. Cook;V. K. Cortessis;E. D. Crawford;O. Cussenot;F. G. Davis;I. De Vivo;X. Deng;T. Ding;C. P. Dinney;A. L. Di Stefano;W. R. Diver;E. J. Duell;J. W. Elena;J. Fan;H. S. Feigelson;M. Feychting;J. D. Figueroa;A. M. Flanagan;J. F. Fraumeni;N. D. Freedman;B. L. Fridley;C. S. Fuchs;M. Gago Dominguez;S. Gallinger;Y. Gao;S. M. Gapstur;M. Garcia Closas;R. Garcia Closas;J. M. Gastier Foster;J. M. Gaziano;D. S. Gerhard;C. A. Giffen;G. G. Giles;E. M. Gillanders;E. L. Giovannucci;M. Goggins;N. Gokgoz;A. M. Goldstein;C. Gonzalez;R. Gorlick;M. H. Greene;M. Gross;H. B. Grossman;R. Grubb;J. Gu;P. Guan;C. A. Haiman;G. Hallmans;S. E. Hankinson;C. C. Harris;P. Hartge;C. Hattinger;R. B. Hayes;Q. He;L. Helman;B. E. Henderson;R. Henriksson;J. Hoffman Bolton;C. Hohensee;E. A. Holly;Y. Hong;R. N. Hoover;H. D. Hosgood;C. Hsiao;A. W. Hsing;C. A. Hsiung;N. Hu;W. Hu;Z. Hu;M. Huang;D. J. Hunter;P. D. Inskip;H. Ito;E. J. Jacobs;K. B. Jacobs;M. Jenab;B. Ji;C. Johansen;M. Johansson;A. Johnson;R. Kaaks;A. M. Kamat;A. Kamineni;M. Karagas;C. Khanna;K. Khaw;C. Kim;I. Kim;Y. H. Kim;Y. Kim;Y. T. Kim;C. H. Kang;Y. J. Jung;C. M. Kitahara;A. P. Klein;R. Klein;M. Kogevinas;W. Koh;T. Kohno;L. N. Kolonel;C. Kooperberg;C. P. Kratz;V. Krogh;H. Kunitoh;R. C. Kurtz;N. Kurucu;Q. Lan;M. Lathrop;C. C. Lau;F. Lecanda;K. Lee;M. P. Lee;L. Le Marchand;S. P. Lerner;D. Li;L. M. Liao;W. Lim;D. Lin;J. Lin;S. Lindstrom;M. S. Linet;J. Lissowska;J. Liu;B. Ljungberg;J. Lloreta;D. Lu;J. Ma;N. Malats;S. Mannisto;N. Marina;G. Mastrangelo;K. Matsuo;K. A. McGlynn;R. McKean Cowdin;L. H. McNeill;R. R. McWilliams;B. S. Melin;P. S. Meltzer;J. E. Mensah;X. Miao;D. S. Michaud;A. M. Mondul;L. E. Moore;K. Muir;S. Niwa;S. H. Olson;N. Orr;S. Panico;J. Y. Park;A. V. Patel;A. Patino Garcia;S. Pavanello;P. H. M. Peeters;B. Peplonska;U. Peters;G. M. Petersen;P. Picci;M. C. Pike;S. Porru;J. Prescott;X. Pu;M. P. Purdue;Y. Qiao;P. Rajaraman;E. Riboli;H. A. Risch;R. J. Rodabough;N. Rothman;A. M. Ruder;J. Ryu;M. Sanson;A. Schned;F. R. Schumacher;A. G. Schwartz;K. L. Schwartz;M. Schwenn;K. Scotlandi;A. Seow;C. Serra;M. Serra;H. D. Sesso;G. Severi;H. Shen;M. Shen;S. Shete;K. Shiraishi;X. Shu;A. Siddiq;L. Sierrasesumaga;S. Sierri;A. D. Loon Sihoe;D. T. Silverman;M. Simon;M. C. Southey;L. Spector;M. Spitz;M. Stampfer;P. Stattin;M. C. Stern;V. L. Stevens;R. Z. Stolzenberg Solomon;D. O. Stram;S. S. Strom;W. Su;M. Sund;S. W. Sung;A. Swerdlow;W. Tan;H. Tanaka;W. Tang;Z. Tang;A. Tardon;E. Tay;P. R. Taylor;Y. Tettey;D. M. Thomas;R. Tirabosco;A. Tjonneland;G. S. Tobias;J. R. Toro;R. C. Travis;D. Trichopoulos;R. Troisi;A. Truelove;Y. Tsai;M. A. Tucker;R. Tumino;D. Van Den Berg;S. K. Van Den Eeden;R. Vermeulen;P. Vineis;K. Visvanathan;U. Vogel;C. Wang;C. Wang;J. Wang;S. S. Wang;E. Weiderpass;S. J. Weinstein;N. Wentzensen;W. Wheeler;E. White;J. K. Wiencke;A. Wolk;B. M. Wolpin;M. P. Wong;M. Wrensch;C. Wu;T. Wu;X. Wu;Y. Wu;J. S. Wunder;Y. Xiang;J. Xu;H. P. Yang;P. Yang;Y. Yatabe;Y. Ye;E. D. Yeboah;Z. Yin;C. Ying;C. Yu;K. Yu;J. Yuan;K. A. Zanetti;A. Zeleniuch Jacquotte;W. Zheng;B. Zhou;L. Mirabello;S. A. Savage;P. Kraft;S. J. Chanock;M. Yeager;M. T. Landi;J. Shi;N. Chatterjee;L. T. Amundadottir

2014

Abstract

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

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	Settori scientifico-disciplinari dell'articolo
	
			Settore MED/44 - Medicina del Lavoro
		
	Data di pubblicazione
	
			15-dic-2014
		
	Rivista in ANCE
	
			HUMAN MOLECULAR GENETICS
		
	DOI
	
			https://dx.doi.org/10.1093/hmg/ddu363
		
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			01 - Articolo su periodico

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