Shared heritability and functional enrichment across six solid cancers.
Xia Jiang,
Hilary K Finucane,
Fredrick R Schumacher,
Stephanie L Schmit,
Jonathan P Tyrer,
Younghun Han,
Kyriaki Michailidou,
Corina Lesseur,
Karoline B Kuchenbaecker,
Joe Dennis,
David V Conti,
Graham Casey,
Mia M Gaudet,
Jeroen R Huyghe,
Demetrius Albanes,
Melinda C Aldrich,
Angeline S Andrew,
Irene L Andrulis,
Hoda Anton-Culver,
Antonis C Antoniou,
Natalia N Antonenkova,
Susanne M Arnold,
Kristan J Aronson,
Banu K Arun,
Elisa V Bandera,
Rosa B Barkardottir,
Daniel R Barnes,
Jyotsna Batra,
Matthias W Beckmann,
Javier Benitez,
Sara Benlloch,
Andrew Berchuck,
Sonja I Berndt,
Heike Bickeböller,
Stephanie A Bien,
Carl Blomqvist,
Stefania Boccia,
Natalia V Bogdanova,
Stig E Bojesen,
Manjeet K Bolla,
Hiltrud Brauch,
Hermann Brenner,
James D Brenton,
Mark N Brook,
Joan Brunet,
Hans Brunnström,
Daniel D Buchanan,
Barbara Burwinkel,
Ralf Butzow,
Gabriella Cadoni,
Trinidad Caldés,
Maria A Caligo,
Ian Campbell,
Peter T Campbell,
Géraldine Cancel-Tassin,
Lisa Cannon-Albright,
Daniele Campa,
Neil Caporaso,
André L Carvalho,
Andrew T Chan,
Jenny Chang-Claude,
Stephen J Chanock,
Chu Chen,
David C Christiani,
Kathleen B M Claes,
Frank Claessens,
Judith Clements,
J Margriet Collée,
Marcia Cruz Correa,
Fergus J Couch,
Angela Cox,
Julie M Cunningham,
Cezary Cybulski,
Kamila Czene,
Mary B Daly,
Anna deFazio,
Peter Devilee,
Orland Diez,
Manuela Gago-Dominguez,
Jenny L Donovan,
Thilo Dörk,
Eric J Duell,
Alison M Dunning,
Miriam Dwek,
Diana M Eccles,
Christopher K Edlund,
Digna R Velez Edwards,
Carolina Ellberg,
D Gareth Evans,
Peter A Fasching,
Robert L Ferris,
Triantafillos Liloglou,
Jane C Figueiredo,
Olivia Fletcher,
Renée T Fortner,
Florentia Fostira,
Silvia Franceschi,
Eitan Friedman,
Steven J Gallinger,
Patricia A Ganz,
Judy Garber,
José A García-Sáenz,
Simon A Gayther,
Graham G Giles,
Andrew K Godwin,
Mark S Goldberg,
David E Goldgar,
Ellen L Goode,
Marc T Goodman,
Gary Goodman,
Kjell Grankvist,
Mark H Greene,
Henrik Gronberg,
Jacek Gronwald,
Pascal Guénel,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Freddie C Hamdy,
Robert J Hamilton,
Jochen Hampe,
Aage Haugen,
Florian Heitz,
Rolando Herrero,
Peter Hillemanns,
Michael Hoffmeister,
Estrid Høgdall,
Yun-Chul Hong,
John L Hopper,
Richard Houlston,
Peter J Hulick,
David J Hunter,
David G Huntsman,
Gregory Idos,
Evgeny N Imyanitov,
Sue Ann Ingles,
Claudine Isaacs,
Anna Jakubowska,
Paul James,
Mark A Jenkins,
Mattias Johansson,
Mikael Johansson,
Esther M John,
Amit D Joshi,
Radka Kaneva,
Beth Y Karlan,
Linda E Kelemen,
Tabea Kühl,
Kay-Tee Khaw,
Elza Khusnutdinova,
Adam S Kibel,
Lambertus A Kiemeney,
Jeri Kim,
Susanne K Kjaer,
Julia A Knight,
Manolis Kogevinas,
Zsofia Kote-Jarai,
Stella Koutros,
Vessela N Kristensen,
Jolanta Kupryjanczyk,
Martin Lacko,
Stephan Lam,
Diether Lambrechts,
Maria Teresa Landi,
Philip Lazarus,
Nhu D Le,
Eunjung Lee,
Flavio Lejbkowicz,
Heinz-Josef Lenz,
Goska Leslie,
Davor Lessel,
Jenny Lester,
Douglas A Levine,
Li Li,
Christopher I Li,
Annika Lindblom,
Noralane M Lindor,
Geoffrey Liu,
Fotios Loupakis,
Jan Lubiński,
Lovise Maehle,
Christiane Maier,
Arto Mannermaa,
Loic Le Marchand,
Sara Margolin,
Taymaa May,
Lesley McGuffog,
Alfons Meindl,
Pooja Middha,
Austin Miller,
Roger L Milne,
Robert J MacInnis,
Francesmary Modugno,
Marco Montagna,
Victor Moreno,
Kirsten B Moysich,
Lorelei Mucci,
Kenneth Muir,
Anna Marie Mulligan,
Katherine L Nathanson,
David E Neal,
Andrew R Ness,
Susan L Neuhausen,
Heli Nevanlinna,
Polly A Newcomb,
Lisa F Newcomb,
Finn Cilius Nielsen,
Liene Nikitina-Zake,
Børge G Nordestgaard,
Robert L Nussbaum,
Kenneth Offit,
Edith Olah,
Ali Amin Al Olama,
Olufunmilayo I Olopade,
Andrew F Olshan,
Håkan Olsson,
Ana Osorio,
Hardev Pandha,
Jong Y Park,
Nora Pashayan,
Michael T Parsons,
Tanja Pejovic,
Kathryn L Penney,
Wilbert H M Peters,
Catherine M Phelan,
Amanda I Phipps,
Dijana Plaseska-Karanfilska,
Miranda Pring,
Darya Prokofyeva,
Paolo Radice,
Kari Stefansson,
Susan J Ramus,
Leon Raskin,
Gad Rennert,
Hedy S Rennert,
Elizabeth J van Rensburg,
Marjorie J Riggan,
Harvey A Risch,
Angela Risch,
Monique J Roobol,
Barry S Rosenstein,
Mary Anne Rossing,
Kim De Ruyck,
Emmanouil Saloustros,
Dale P Sandler,
Elinor J Sawyer,
Matthew B Schabath,
Johanna Schleutker,
Marjanka K Schmidt,
V Wendy Setiawan,
Hongbing Shen,
Erin M Siegel,
Weiva Sieh,
Christian F Singer,
Martha L Slattery,
Karina Dalsgaard Sorensen,
Melissa C Southey,
Amanda B Spurdle,
Janet L Stanford,
Victoria L Stevens,
Sebastian Stintzing,
Jennifer Stone,
Karin Sundfeldt,
Rebecca Sutphen,
Anthony J Swerdlow,
Eloiza H Tajara,
Catherine M Tangen,
Adonina Tardon,
Jack A Taylor,
M Dawn Teare,
Manuel R Teixeira,
Mary Beth Terry,
Kathryn L Terry,
Stephen N Thibodeau,
Mads Thomassen,
Line Bjørge,
Marc Tischkowitz,
Amanda E Toland,
Diana Torres,
Paul A Townsend,
Ruth C Travis,
Nadine Tung,
Shelley S Tworoger,
Cornelia M Ulrich,
Nawaid Usmani,
Celine M Vachon,
Els Van Nieuwenhuysen,
Ana Vega,
Miguel Elías Aguado-Barrera,
Qin Wang,
Penelope M Webb,
Clarice R Weinberg,
Stephanie Weinstein,
Mark C Weissler,
Jeffrey N Weitzel,
Catharine M L West,
Emily White,
Alice S Whittemore,
H-Erich Wichmann,
Fredrik Wiklund,
Robert Winqvist,
Alicja Wolk,
Penella Woll,
Michael Woods,
Anna H Wu,
Xifeng Wu,
Drakoulis Yannoukakos,
Wei Zheng,
Shanbeh Zienolddiny,
Argyrios Ziogas,
Kristin K Zorn,
Jacqueline M Lane,
Richa Saxena,
Duncan Thomas,
Rayjean J Hung,
Brenda Diergaarde,
James McKay,
Ulrike Peters,
Li Hsu,
Montserrat García-Closas,
Rosalind A Eeles,
Georgia Chenevix-Trench,
Paul J Brennan,
Christopher A Haiman,
Jacques Simard,
Douglas F Easton,
Stephen B Gruber,
Paul D P Pharoah,
Alkes L Price,
Bogdan Pasaniuc,
Christopher I Amos,
Peter Kraft,
Sara Lindström
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.