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Hum Mol Genet. 2015 Oct 1;24(19):5589-602. doi: 10.1093/hmg/ddv203. Epub 2015 May 29.

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.

Collaborators (803)

Cook M, Morgan A, Lophatananon A, Fisher C, Sawyer EJ, Tymrakiewicz M, Livni N, Wilkinson R, Jugurnauth-Little S, Hazel S, Severi G, Pedersen J, Southey MC, Fitzgerlad LM, Hopper JL, Karlsson A, Cavalli-Bjoerkman C, Johansson JE, Adolfson J, Aly M, Broms M, Stattin P, Henderson BE, Schumacher F, Auvinen A, Taari K, Maeaettaenen L, Kujala P, Murtola T, Tammela TL, Wahlfors T, Weischer M, Roder A, Iversen P, Klarskov P, Nielsen SF, Key TJ, Wallinder H, Gustafsson S, Donovan JL, Hamdy F, Cox A, George A, Lane A, Marsden G, Davis M, Brown P, Pharoah P, Holt S, Signorello LB, Zheng W, McDonnell SK, Schaid DJ, Wang L, Tillmans L, Riska S, Rinckleb A, Herkommer K, Luedeke M, Vogel W, Wokozorczyk D, Lubinski J, Kluzniak W, Stegmaier C, Zachariah B, Lim HY, Park H, Haley J, Pow-Sang J, Rincon M, Radlein S, Sellers T, Vlahova A, Mitkova A, Slavov C, Kachakova D, Popov E, Christova S, Dikov T, Mitev V, Eckert A, Spurdle A, Collins A, Wood G, Malone G, Clements JA, Alexander K, Kerr K, Kedda MA, Turner M, Saunders P, Heathcote P, Srinivasan S, Omara T, Yeadon T, Santos J, Barros-Silva J, Paulo P, Pinto P, Henrique R, Maia S, Michael A, Kierzek A, Wu H, Abbasi Z, Abdul-Hamid MA, Abel PD, Abrams PH, Adab FA, Adamson A, Adeyoju A, Afzal N, Ahiaku EK, Ahmed M, Al Sudani ML, Alcock C, Ali Z, Almond DJ, Alonzi R, Al-Samarraie AS, Al-Samerraie, Al-Singary W, Al-Sudani, Anderson J, Andrews S, Andrews H, Anjum I, Anson K, Anyamene NA, Apakama I, Aparcia F, Archbold JA, Ash D, Ashford RF, Azzabi A, Badenoch D, Bahl A, Bailey MJ, Bailey K, Ball AJ, Banerjee G, Barber N, Barber J, Baria, Barnes DG, Bashir J, Basu P, Bates CA, Bax NA, Baxter-Smith D, Bdesha A, Beacock CJ, Beaney RP, Beard R, Beatty JD, Beck R, Beese G, Beesley S, Bell CR, Bellringer J, Benson R, Beresford, Bevis CR, Bhana R, Bhanot S, Bhatnagar A, Bhatt RI, Birch B, Birtle A, Bishop M, Biyani CS, Blacklock AR, Blades R, Bliss P, Bloomfield DJ, Boddy S, Booth CM, Bose P, Bott MC, Bottomley D, Boucher NR, Bowen J, Bower M, Bowsher WG, Boyd PJ, Bramble FJ, Brewster SF, Briggs T, Brock C, Brock S, Bromage S, Brough R, Brown R, Brown S, Brown R, Browning TJ, Bryan N, Burgess NA, Burns-Cox N, Butterworth PC, Cahill D, Callaghan PS, Calleary J, Calleja M, Calman F, Camilleri P, Campbell A, Cannon A, Carnell DM, Carr TW, Carter S, Carter CJ, Carter AC, Castle BM, Chadwick D, Chahal R, Chakraborti P, Chappell, Charig C, Chetiyawardana AD, Chilton C, Chinegwundoh FI, Chong I, Choudhury A, Chow WM, Christmas TJ, Churn MJ, Clarke NW, Clavijo-Eisele J, Coe M, Cohen NP, Coker C, Cole T, Cole DJ, Cole O, Collins G, Collinson M, Conn I, Connell C, Cook A, Cooke P, Cooksey G, Coombs L, Copland RF, Cornaby AJ, Cornford PA, Corolis, Corr J, Costello CB, Coull MN, Cowan R, Cox R, Coyle C, Crew J, Crisp JC, Cross W, Cross W, Cruger D, Crundwell M, Cummings, Dahar N, Daniel FN, Darrad J, Daruwala P, Das G, Datta S, Davidson S, Davies J, Davison OW, Dawkins G, Dawson C, De Bolla AR, Dearnaley D, Desai KM, Deutsch GP, Dick J, Dickinson AJ, Dickson J, Dinneen M, Dixit S, Dobbs HJ, Doble A, Dodds D, Doherty A, Donaldson P, Dooldeniya M, Douglas SF, Drake, Duchesne GM, Duffy P, Dunn M, Dunsmuir WD, Durrani SK, Eaton AC, Eccles D, Eddy B, Eden CD, Edwards J, Elkabir J, Elliott PT, Ellis BW, Ellis R, El-Modir A, Elves AW, Elwell C, Emberton M, Emmerson L, England RC, Errington RD, Evans DG, Falconer A, Fawcett D, Featherston C, Featherstone CJ, Feggetter J, Ferguson C, Fermont D, Ferro M, Fletcher M, Folkes A, Ford TF, Foster PW, Franks KN, Frim O, Gale J, Gallegos C, Gelister JS, Ghana, Gibbs S, Gilbert H, Gillatt D, Glaholm J, Glass JM, Glenister J, Goode TD, Gordon EM, Gower RL, Graham J, Green D, Greenland J, Grieve R, Griffiths TR, Gujral S, Gupta N, Gurun RM, Guy PJ, Haldar N, Halder N, Hamdy FC, Hamilton C, Hammonds J, Hampson SJ, Hanbury DC, Hardman PD, Harland SJ, Harney JM, Harper P, Harris S, Harris D, Harrison GS, Harriss DR, Harvey-Hills N, Hawkyard S, Heath CM, Hehir M, Hellawell GO, Hendry D, Henley M, Henry A, Hetherington J, Hickish T, Hicks JA, Hilman S, Hindley R, Hindmarsh JR, Hines J, Hingorani M, Ho ET, Hodgson S, Hoffman U, Holden D, Hollingdale A, Hollins GW, Holmes SA, Horan G, Horwich A, Hoskin P, Howell GP, Hrouda D, Huddart R, Hudson L, Hughes R, Hughes M, Hughes O, Humber C, Iacovou JW, Ibrahim A, Inglis JA, Irving S, Irwin C, Izatt L, Izegbu V, Jameel B, James MJ, James N, James RL, Javle P, Jenkins P, Jhavar S, Jones G, Jones CR, Jones DA, Joseph J, Joss S, Kaisary A, Kaliski AL, Kapur G, Karim O, Karp SJ, Keeley FX, Kelkar AR, Kelleher JP, Kelly J, Kenwrick S, Khan F, Khoo V, Kimber RM, Kinder R, Kirby RS, Kirk D, Kirkbride P, Kirollos MM, Kockelbergh R, Koenig PC, Kooiman GG, Koreich O, Koupparis A, Kourah M, Kraus S, Kujawa ML, Kulkarni R, Kumar M, Kunkler IH, Kynaston H, Lachlan KL, Laing R, Lalloo F, Lancashire M, Langley SE, Laniado M, Larner TR, Lau MW, Lawrence WT, Lawson A, Le Roux PJ, Leader M, Lee JO, Lee L, Lee A, Lemburger RJ, Leone P, Lester J, Leung H, Lewis J, Lewis DC, Liston T, Livsey J, Lloyd S, Locke I, Lodge R, Logue J, Longmuir M, Lucas MG, Luscombe CJ, Lydon A, Lynch M, Lynn NN, MacDermott JP, Macdonagh RP, Macdonald, Madaan S, Madhava KR, Maguire J, Maher ER, Mahmood R, Mair GH, Malone PR, Mangar SA, Mantle M, Mark I, Mason R, Mason MD, Matanhelia, Matenhelia S, Matthews PN, McAleese J, McBride D, McFarlane J, McGrath, McIlhenny C, McInerney P, McIntosh G, McKinna F, McLaren D, McLarty E, McMenemin R, McNeill A, McNicholas TA, Meddings RN, Mee AD, Melcher L, Memon, Menzes P, Miller M, Mills R, Mitchell S, Mithal N, Mitra A, Mobb GE, Moffat LE, Mokete, Money-Kyrle J, Montgomery B, Moody MP, Morley R, Morris SB, Morrison P, Mort D, Mostafid AH, Motiwala H, Mufti G, Muir G, Mumtaz F, Murphy M, Murray KW, Murray A, Murrell S, Muthukumar D, Naerger H, Namasivayam S, Nargund V, Nawrocki, Neilson D, Nethersell A, Barwell J, Newby JC, Newman H, Newton R, Oakley N, O'Boyle PJ, O'Brien J, O'Brien TS, O'Donnell H, O'Donoghue N, O'Donoghue E, Ogden C, Ohja H, Oliver T, Ong EK, O'Reilly P, O'Rourke JS, Osborn D, Ostler P, O'Sullivan J, Owen J, Palfrey E, Panades M, Panakis N, Pancharatnam M, Pantelides ML, Panwar U, Parikh O, Parker C, Parker CH, Parys BT, Pascoe S, Patel A, Paterson J, Pathack S, Pati J, Patterson H, Pattu, Paul A, Payne H, Peake D, Pedley I, Pengelly A, Peracha AM, Perry M, Persad R, Peters J, Philp NH, Philp T, Pickering LM, Pigott K, Plail R, Plowman PN, Pocock RD, Pope AJ, Popert R, Porter T, Potter JM, Powell C, Powles TB, Prasad K, Prasad SS, Prejbisz JW, Prescott S, Protheroe A, Qureshi KN, Raby N, Ragavan N, Raju PG, Ramachandra PB, Raman R, Rane A, Rankin J, Rao Y, Ratan HL, Ravi R, Ravishankar K, Read, Reddy PJ, Rimington PR, Ritchie PA, Roberts JT, Robertson A, Robinson A, Robinson AC, Robinson LQ, Rochester MA, Rogers PB, Rosenbaum TP, Rothwell N, Rowbotham C, Rowe, Rowley K, Ruddy D, Rundle J, Russell JM, Ryan PG, Sabharwal A, Saggar AK, Samanci A, Sangar VK, Saxby MF, Schwaibold H, Scoble JE, Scrase C, Selim, Sells H, Sethia KK, Shackley DC, Shaffer, Shah N, Shakespeare D, Shanley S, Sharma NK, Sheehan DJ, Sherwin E, Shum PL, Side L, Sidek N, Sikora K, Simcock R, Sinclair AM, Singh P, Siva M, Smith MF, Smith J, Sokal M, Sole GM, Speakman MJ, Spiers A, Sreenivasan T, Srihari NN, Srinivasan, Sriram R, Staffurth JN, Stewart D, Stockdale A, Stott MA, Stower MJ, Strachan JR, Stuart NS, Sugden E, Summerton D, Sundar S, Sundaram SK, Suresh G, Susnerwala S, Swami KS, Symons SJ, Syndikus I, Tahir S, Tanquay J, Taylor JW, Taylor JW, Terry T, Thomas RJ, Thomas SA, Thompson A, Thomson AH, Thurston A, Tilsley O, Tindall SF, Tipples K, Tong, Toussi H, Toy EW, Trembath RC, Tulloch DN, Turner KJ, Tweedle J, Tyrell CJ, Umez-Eronini N, Urwin GH, Vale JA, Van As, Van As N, Vasanthan S, Vesey S, Vilarino-Varela M, Violet J, Virdi J, Wade R, Waite K, Walker EM, Walker R, Wallace DM, Watkin NA, Watson ME, Waxman JH, Waymont B, Weaver A, Webb RJ, Wedderburn A, Wells P, Wemyss-Holden GD, Weston PM, Wheatley D, Whelan P, Whillis D, Wilde AD, Wiles V, Wilkins M, Williams JH, Williams S, Willis M, Wills MI, Wilson R, Wilson JR, Winkler MH, Wise M, Woodhams S, Woodhouse C, Woodward C, Woolf, Woolfenden KA, Worlding J, Wright M, WYLIE, Wylie JP, Wynne C, Zang A, Zarkar A, Cox A, Brown PM, George A, Marsden G, Lane A, Davis M, Bollina P, Bonnington S, Bradshaw L, Catto J, Cooper D, Down L, Doble A, Doherty A, Durkan G, Elliott E, Gillatt D, Herbert P, Holding P, Howson J, Jones M, Kockelbergh R, Kumar R, Kynaston H, Lane A, Lennon T, Lyons N, Leung H, Mason M, Moody H, Powell P, Paul A, Prescott S, Rosario D, O'Sullivan P, Thompson P, Tidball S.

Abstract

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region.

PMID:
26025378
PMCID:
PMC4572072
DOI:
10.1093/hmg/ddv203
[Indexed for MEDLINE]
Free PMC Article

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