Shared heritability and functional enrichment across six solid cancers.

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.

Metadata

Item Type:	Article
Authors/Creators:	Jiang, X Finucane, HK https://orcid.org/0000-0003-3864-9828 Schumacher, FR https://orcid.org/0000-0002-3073-7463 Schmit, SL https://orcid.org/0000-0001-5931-1194 Tyrer, JP Han, Y Michailidou, K https://orcid.org/0000-0001-7065-1237 Lesseur, C Kuchenbaecker, KB https://orcid.org/0000-0001-9726-603X Dennis, J https://orcid.org/0000-0003-4591-1214 Conti, DV Casey, G Gaudet, MM Huyghe, JR https://orcid.org/0000-0001-6027-9806 Albanes, D Aldrich, MC Andrew, AS Andrulis, IL https://orcid.org/0000-0002-4226-6435 Anton-Culver, H Antoniou, AC Antonenkova, NN Arnold, SM https://orcid.org/0000-0001-6542-9551 Aronson, KJ Arun, BK Bandera, EV Barkardottir, RB Barnes, DR https://orcid.org/0000-0002-3781-7570 Batra, J https://orcid.org/0000-0003-4646-6247 Beckmann, MW Benitez, J Benlloch, S Berchuck, A Berndt, SI Bickeböller, H Bien, SA Blomqvist, C Boccia, S Bogdanova, NV Bojesen, SE https://orcid.org/0000-0002-4061-4133 Bolla, MK Brauch, H https://orcid.org/0000-0001-7531-2736 Brenner, H Brenton, JD https://orcid.org/0000-0002-5738-6683 Brook, MN https://orcid.org/0000-0002-8969-2378 Brunet, J https://orcid.org/0000-0003-1945-3512 Brunnström, H https://orcid.org/0000-0001-7402-138X Buchanan, DD https://orcid.org/0000-0003-2225-6675 Burwinkel, B Butzow, R Cadoni, G Caldés, T Caligo, MA Campbell, I https://orcid.org/0000-0002-7773-4155 Campbell, PT Cancel-Tassin, G https://orcid.org/0000-0002-9583-6382 Cannon-Albright, L Campa, D Caporaso, N Carvalho, AL Chan, AT https://orcid.org/0000-0001-7284-6767 Chang-Claude, J Chanock, SJ https://orcid.org/0000-0002-2324-3393 Chen, C Christiani, DC Claes, KBM https://orcid.org/0000-0003-0841-7372 Claessens, F Clements, J Collée, JM Correa, MC Couch, FJ Cox, A Cunningham, JM https://orcid.org/0000-0002-8159-3025 Cybulski, C Czene, K Daly, MB deFazio, A Devilee, P https://orcid.org/0000-0002-8023-2009 Diez, O Gago-Dominguez, M Donovan, JL Dörk, T Duell, EJ Dunning, AM Dwek, M Eccles, DM Edlund, CK Edwards, DRV Ellberg, C https://orcid.org/0000-0001-7297-0645 Evans, DG Fasching, PA https://orcid.org/0000-0003-4885-8471 Ferris, RL Liloglou, T https://orcid.org/0000-0003-0460-1404 Figueiredo, JC Fletcher, O https://orcid.org/0000-0001-9387-7116 Fortner, RT Fostira, F Franceschi, S Friedman, E Gallinger, SJ Ganz, PA Garber, J García-Sáenz, JA https://orcid.org/0000-0001-6880-0301 Gayther, SA Giles, GG Godwin, AK Goldberg, MS Goldgar, DE Goode, EL Goodman, MT Goodman, G Grankvist, K https://orcid.org/0000-0003-4289-2097 Greene, MH https://orcid.org/0000-0003-1852-9239 Gronberg, H https://orcid.org/0000-0002-1073-2753 Gronwald, J Guénel, P https://orcid.org/0000-0002-8359-518X Håkansson, N Hall, P Hamann, U Hamdy, FC Hamilton, RJ Hampe, J https://orcid.org/0000-0002-2421-6127 Haugen, A Heitz, F Herrero, R Hillemanns, P Hoffmeister, M Høgdall, E Hong, Y-C Hopper, JL Houlston, R https://orcid.org/0000-0002-5268-0242 Hulick, PJ https://orcid.org/0000-0001-8397-4078 Hunter, DJ Huntsman, DG Idos, G Imyanitov, EN Ingles, SA Isaacs, C Jakubowska, A James, P https://orcid.org/0000-0002-4361-4657 Jenkins, MA https://orcid.org/0000-0002-8964-6160 Johansson, M Johansson, M John, EM Joshi, AD https://orcid.org/0000-0001-7581-6934 Kaneva, R Karlan, BY Kelemen, LE Kühl, T Khaw, K-T 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 https://orcid.org/0000-0002-3429-302X Landi, MT Lazarus, P Le, ND Lee, E Lejbkowicz, F Lenz, H-J Leslie, G https://orcid.org/0000-0001-5756-6222 Lessel, D https://orcid.org/0000-0003-4496-244X Lester, J Levine, DA https://orcid.org/0000-0003-1038-8232 Li, L Li, CI Lindblom, A Lindor, NM Liu, G Loupakis, F Lubiński, J Maehle, L Maier, C Mannermaa, A Marchand, LL Margolin, S May, T McGuffog, L Meindl, A Middha, P Miller, A https://orcid.org/0000-0001-9739-8462 Milne, RL https://orcid.org/0000-0001-5764-7268 MacInnis, RJ Modugno, F Montagna, M Moreno, V https://orcid.org/0000-0002-2818-5487 Moysich, KB Mucci, L Muir, K https://orcid.org/0000-0001-6429-988X Mulligan, AM Nathanson, KL https://orcid.org/0000-0002-6740-0901 Neal, DE Ness, AR Neuhausen, SL Nevanlinna, H https://orcid.org/0000-0002-0916-2976 Newcomb, PA https://orcid.org/0000-0001-8786-0043 Newcomb, LF Nielsen, FC Nikitina-Zake, L https://orcid.org/0000-0003-2491-5187 Nordestgaard, BG https://orcid.org/0000-0002-1954-7220 Nussbaum, RL Offit, K Olah, E Olama, AAA https://orcid.org/0000-0002-7178-3431 Olopade, OI https://orcid.org/0000-0002-9936-1599 Olshan, AF Olsson, H Osorio, A Pandha, H Park, JY Pashayan, N https://orcid.org/0000-0003-0843-2468 Parsons, MT https://orcid.org/0000-0003-3242-8477 Pejovic, T Penney, KL Peters, WHM Phelan, CM Phipps, AI Plaseska-Karanfilska, D https://orcid.org/0000-0001-8877-2416 Pring, M Prokofyeva, D Radice, P Stefansson, K Ramus, SJ Raskin, L https://orcid.org/0000-0003-1195-7214 Rennert, G https://orcid.org/0000-0002-8512-068X Rennert, HS van Rensburg, EJ Riggan, MJ Risch, HA Risch, A https://orcid.org/0000-0002-8026-5505 Roobol, MJ https://orcid.org/0000-0001-6967-1708 Rosenstein, BS Rossing, MA De Ruyck, K Saloustros, E https://orcid.org/0000-0002-0485-0120 Sandler, DP Sawyer, EJ Schabath, MB https://orcid.org/0000-0003-3241-3216 Schleutker, J https://orcid.org/0000-0002-1863-0305 Schmidt, MK https://orcid.org/0000-0002-2228-429X Setiawan, VW Shen, H Siegel, EM Sieh, W Singer, CF Slattery, ML Sorensen, KD https://orcid.org/0000-0002-4902-5490 Southey, MC Spurdle, AB Stanford, JL Stevens, VL Stintzing, S https://orcid.org/0000-0002-3297-5801 Stone, J https://orcid.org/0000-0001-5077-0124 Sundfeldt, K Sutphen, R Swerdlow, AJ Tajara, EH Tangen, CM Tardon, A https://orcid.org/0000-0001-5150-1209 Taylor, JA Teare, MD https://orcid.org/0000-0003-3994-0051 Teixeira, MR https://orcid.org/0000-0002-4896-5982 Terry, MB Terry, KL Thibodeau, SN Thomassen, M Bjørge, L Tischkowitz, M Toland, AE https://orcid.org/0000-0002-0271-1792 Torres, D Townsend, PA Travis, RC Tung, N Tworoger, SS Ulrich, CM Usmani, N Vachon, CM Van Nieuwenhuysen, E Vega, A Aguado-Barrera, ME https://orcid.org/0000-0002-7822-6726 Wang, Q Webb, PM https://orcid.org/0000-0003-0733-5930 Weinberg, CR Weinstein, S Weissler, MC Weitzel, JN West, CML White, E Whittemore, AS Wichmann, H-E Wiklund, F Winqvist, R Wolk, A https://orcid.org/0000-0001-7387-6845 Woll, P Woods, M Wu, AH Wu, X Yannoukakos, D https://orcid.org/0000-0001-7509-3510 Zheng, W https://orcid.org/0000-0003-1226-070X Zienolddiny, S Ziogas, A https://orcid.org/0000-0003-4529-3727 Zorn, KK Lane, JM Saxena, R Thomas, D Hung, RJ Diergaarde, B McKay, J Peters, U https://orcid.org/0000-0001-5666-9318 Hsu, L García-Closas, M Eeles, RA https://orcid.org/0000-0002-3698-6241 Chenevix-Trench, G Brennan, PJ https://orcid.org/0000-0002-0518-8714 Haiman, CA Simard, J Easton, DF https://orcid.org/0000-0003-2444-3247 Gruber, SB Pharoah, PDP https://orcid.org/0000-0001-8494-732X Price, AL https://orcid.org/0000-0002-2971-7975 Pasaniuc, B Amos, CI Kraft, P Lindström, S
Copyright, Publisher and Additional Information:	© 2019 The Authors. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 25 January 2019 Published (online): 25 January 2019 Accepted: 10 December 2018
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Health and Related Research (Sheffield) > ScHARR - Sheffield Centre for Health and Related Research
Funding Information:	Funder Grant number BREAST CANCER NOW UNSPECIFIED CANCER RESEARCH UK C9267/A25152
Depositing User:	Symplectic Sheffield
Date Deposited:	07 Feb 2019 16:13
Last Modified:	13 Mar 2020 13:51
Published Version:	https://doi.org/10.1038/s41467-018-08054-4
Status:	Published
Publisher:	Nature Research
Refereed:	Yes
Identification Number:	10.1038/s41467-018-08054-4
Related URLs:	PubMed URL Erratum/Corrigendum
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:142007

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Shared heritability and functional enrichment across six solid cancers.

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