Shared heritability and functional enrichment across six solid cancers

Jiang X, Finucane HK, Schumacher FR, Schmit SL, Tyrer JP, Han Y, Michailidou K, Lesseur C, Kuchenbaecker KB, Dennis J, Conti DV, Casey G, Gaudet MM, Huyghe JR, Albanes D, Aldrich MC, Andrew AS, Andrulis IL, Anton-Culver H, Antoniou AC, Antonenkova NN, Arnold SM, Aronson KJ, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Batra J, Beckmann MW, Benitez J, Benlloch S, Berchuck A, Berndt SI, Bickeboller H, Bien SA, Blomqvist C, Boccia S, Bogdanova NV, Bojesen SE, Bolla MK, Brauch H, Brenner H, Brenton JD, Brook MN, Brunet J, Brunnstrom H, Buchanan DD, Burwinkel B, Butzow R, Cadoni G, Caldés T, Caligo MA, Campbell I, Campbell PT, Cancel-Tassin G, Cannon-Albright L, Campa D, Caporaso N, Carvalho AL, Chan AT, Chang-Claude J, Chanock SJ, Chen C, Christiani DC, Claes KBM, Claessens F, Clements J, Collée JM, Correa MC, Couch FJ, Cox A, Cunningham JM, Cybulski C, Czene K, Daly MB, deFazio A, Devilee P, Diez O, Gago-Dominguez M, Donovan JL, Dörk T, Duell EJ, Dunning AM, Dwek M, Eccles DM, Edlund CK, Edwards DRV, Ellberg C, Evans DG, Fasching PA, Ferris RL, Liloglou T, Figueiredo JC, Fletcher O, Fortner RT, Fostira F, Franceschi S, Friedman E, Gallinger SJ, Ganz PA, Garber J, García-Sáenz JA, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, Goode EL, Goodman MT, Goodman G, Grankvist K, Greene MH, Gronberg H, Gronwald J, Guénel P, Håkansson N, Hall P, Hamann U, Hamdy FC, Hamilton RJ, Hampe J, Haugen A, Heitz F, Herrero R, Hillemanns P, Hoffmeister M, Høgdall E, Hong YC, Hopper JL, Houlston R, Hulick PJ, Hunter DJ, Huntsman DG, Idos G, Imyanitov EN, Ingles SA, Isaacs C, Jakubowska A, James P, Jenkins MA, Johansson M, John EM, Joshi AD, Kaneva R, Karlan BY, Kelemen LE, Kühl T, Khaw KT, Khusnutdinova E, Kibel AS, Kiemeney LA, Kim J, Kjaer SK, Knight JA, Kogevinas M, Kote-Jarai Z, Koutros S, Kristensen VN, Kupryjanczyk J, Lacko M, Lam S, Lambrechts D, Landi MT, Lazarus P, Le ND, Lee E, Lejbkowicz F, Lenz HJ, Leslie G, Lessel D, Lester J, Levine DA, Li L, Li CI, Lindblom A, Lindor NM, Liu G, Loupakis F, Lubiński J, Maehle L, Maier C, Mannermaa A, Le Marchand L, Margolin S, May T, McGuffog L, Meindl A, Middha P, Miller A, Milne RL, MacInnis RJ, Modugno F, Montagna M, Moreno V, Moysich KB, Mucci L, Muir K, Mulligan AM, Nathanson KL, Neal DE, Ness AR, Neuhausen SL, Nevanlinna H, Newcomb PA, Newcomb LF, Nielsen FC, Nikitina-Zake L, Nordestgaard BG, Nussbaum RL, Offit K, Olah E, Olama AAA, Olopade OI, Olshan AF, Olsson H, Osorio A, Pandha H, Park JY, Pashayan N, Parsons MT, Pejovic T, Penney KL, Peters WHM, Phelan CM, Phipps AI, Plaseska-Karanfilska D, Pring M, Prokofyeva D, Radice P, Stefansson K, Ramus SJ, Raskin L, Rennert G, Rennert HS, Van Rensburg EJ, Riggan MJ, Risch HA, Risch A, Roobol MJ, Rosenstein BS, Rossing MA, De Ruyck K, Saloustros E, Sandler DP, Sawyer EJ, Schabath MB, Schleutker J, Schmidt MK, Setiawan VW, Shen H, Siegel EM, Sieh W, Singer CF, Slattery ML, Sorensen K D, Southey MC, Spurdle AB, Stanford JL, Stevens VL, Stintzing S, Stone J, Sundfeldt K, Sutphen R, Swerdlow AJ, Tajara EH, Tangen CM, Tardon A, Taylor JA, Teare MD, Teixeira MR, Terry MB, Terry KL, Thibodeau SN, Thomassen M, Bjørge L, Tischkowitz M, Toland AE, Torres D, Townsend PA, Travis RC, Tung N, Tworoger SS, Ulrich CM, Usmani N, Vachon CM, Van Nieuwenhuysen E, Vega A, Aguado-Barrera ME, Wang Q, Webb PM, Weinberg CR, Weinstein S, Weissler MC, Weitzel JN, West CML, White E, Whittemore AS, Wichmann HE, Wiklund F
January 2019
DOI

Abstract

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5), breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15, p = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

Type
Journal article
Publication
Nature Communications 2019; 10:431
Teare

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