Shared heritability and functional enrichment across six solid cancers
Authors: Jiang Xia , Finucane Hilary K. , Schumacher Fredrick R. , Schmit Stephanie L. , Tyrer Jonathan P. , Han Younghun , Michailidou Kyriaki , Lesseur Corina , Kuchenbaecker Karoline B. , Dennis Joe , Conti David V. , Casey Graham , Gaudet Mia M. , Huyghe Jeroen R. , Albanes Demetrius , Aldrich Melinda C. , Andrew Angeline S. , Andrulis Irene L. , Anton-Culver Hoda , Antoniou Antonis C. , Antonenkova Natalia N. , Arnold Susanne M. , Aronson Kristan J. , Arun Banu K. , Bandera Elisa V. , Barkardottir Rosa B. , Barnes Daniel R. , Batra Jyotsna , Beckmann Matthias W. , Benitez Javier , Benlloch Sara , Berchuck Andrew , Berndt Sonja I. , Bickeböller Heike , Bien Stephanie A. , Blomqvist Carl , Boccia Stefania , Bogdanova Natalia V. , Bojesen Stig E. , Bolla Manjeet K. , Brauch Hiltrud , Brenner Hermann , Brenton James D. , Brook Mark N. , Brunet Joan , Brunnström Hans , Buchanan Daniel D. , Burwinkel Barbara , Butzow Ralf , Cadoni Gabriella , Caldés Trinidad , Caligo Maria A. , Campbell Ian , Campbell Peter T. , Cancel-Tassin Géraldine , Cannon-Albright Lisa , Campa Daniele , Caporaso Neil , Carvalho André L. , Chan Andrew T. , Chang-Claude Jenny , Chanock Stephen J. , Chen Chu , Christiani David C. , Claes Kathleen B. M. , Claessens Frank , Clements Judith , Collée J. Margriet , Correa Marcia Cruz , Couch Fergus J. , Cox Angela , Cunningham Julie M. , Cybulski Cezary , Czene Kamila , Daly Mary B. , deFazio Anna , Devilee Peter , Diez Orland , Gago-Dominguez Manuela , Donovan Jenny L. , Dörk Thilo , Duell Eric J. , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Edlund Christopher K. , Edwards Digna R Velez , Ellberg Carolina , Evans D. Gareth , Fasching Peter A. , Ferris Robert L. , Liloglou Triantafillos , Figueiredo Jane C. , Fletcher Olivia , Fortner Renée T. , Fostira Florentia , Franceschi Silvia , Friedman Eitan , Gallinger Steven J. , Ganz Patricia A. , Garber Judy , García-Sáenz José A. , Gayther Simon A. , Giles Graham G. , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , Goode Ellen L. , Goodman Marc T. , Goodman Gary , Grankvist Kjell , Greene Mark H. , Gronberg Henrik , Gronwald Jacek , Guénel Pascal , Håkansson Niclas , Hall Per , Hamann Ute , Hamdy Freddie C. , Hamilton Robert J. , Hampe Jochen , Haugen Aage , Heitz Florian , Herrero Rolando , Hillemanns Peter , Hoffmeister Michael , Høgdall Estrid , Hong Yun-Chul , Hopper John L. , Houlston Richard , Hulick Peter J. , Hunter David J. , Huntsman David G. , Idos Gregory , Imyanitov Evgeny N. , Ingles Sue Ann , Isaacs Claudine , Jakubowska Anna , James Paul , Jenkins Mark A. , Johansson Mattias , Johansson Mikael , John Esther M. , Joshi Amit D. , Kaneva Radka , Karlan Beth Y. , Kelemen Linda E. , Kühl Tabea , Khaw Kay-Tee , Khusnutdinova Elza , Kibel Adam S. , Kiemeney Lambertus A. , Kim Jeri , Kjaer Susanne K. , Knight Julia A. , Kogevinas Manolis , Kote-Jarai Zsofia , Koutros Stella , Kristensen Vessela N. , Kupryjanczyk Jolanta , Lacko Martin , Lam Stephan , Lambrechts Diether , Landi Maria Teresa , Lazarus Philip , Le Nhu D. , Lee Eunjung , Lejbkowicz Flavio , Lenz Heinz-Josef , Leslie Goska , Lessel Davor , Lester Jenny , Levine Douglas A. , Li Li , Li Christopher I. , Lindblom Annika , Lindor Noralane M. , Liu Geoffrey , Loupakis Fotios , Lubiński Jan , Maehle Lovise , Maier Christiane , Mannermaa Arto , Marchand Loic Le , Margolin Sara , May Taymaa , McGuffog Lesley , Meindl Alfons , Middha Pooja , Miller Austin , Milne Roger L. , MacInnis Robert J. , Modugno Francesmary , Montagna Marco , Moreno Victor , Moysich Kirsten B. , Mucci Lorelei , Muir Kenneth , Mulligan Anna Marie , Nathanson Katherine L. , Neal David E. , Ness Andrew R. , Neuhausen Susan L. , Nevanlinna Heli , Newcomb Polly A. , Newcomb Lisa F. , Nielsen Finn Cilius , Nikitina-Zake Liene , Nordestgaard Børge G. , Nussbaum Robert L. , Offit Kenneth , Olah Edith , Olama Ali Amin Al , Olopade Olufunmilayo I. , Olshan Andrew F. , Olsson Håkan , Osorio Ana , Pandha Hardev , Park Jong Y. , Pashayan Nora , Parsons Michael T. , Pejovic Tanja , Penney Kathryn L. , Peters Wilbert H M. , Phelan Catherine M. , Phipps Amanda I. , Plaseska-Karanfilska Dijana , Pring Miranda , Prokofyeva Darya , Radice Paolo , Stefansson Kari , Ramus Susan J. , Raskin Leon , Rennert Gad , Rennert Hedy S. , van Rensburg Elizabeth J. , Riggan Marjorie J. , Risch Harvey A. , Risch Angela , Roobol Monique J. , Rosenstein Barry S. , Rossing Mary Anne , De Ruyck Kim , Saloustros Emmanouil , Sandler Dale P. , Sawyer Elinor J. , Schabath Matthew B. , Schleutker Johanna , Schmidt Marjanka K. , Setiawan V. Wendy , Shen Hongbing , Siegel Erin M. , Sieh Weiva , Singer Christian F. , Slattery Martha L. , Sorensen Karina Dalsgaard , Southey Melissa C. , Spurdle Amanda B. , Stanford Janet L. , Stevens Victoria L. , Stintzing Sebastian , Stone Jennifer , Sundfeldt Karin , Sutphen Rebecca , Swerdlow Anthony J. , Tajara Eloiza H. , Tangen Catherine M. , Tardon Adonina , Taylor Jack A. , Teare M. Dawn , Teixeira Manuel R. , Terry Mary Beth , Terry Kathryn L. , Thibodeau Stephen N. , Thomassen Mads , Bjørge Line , Tischkowitz Marc , Toland Amanda E. , Torres Diana , Townsend Paul A. , Travis Ruth C. , Tung Nadine , Tworoger Shelley S. , Ulrich Cornelia M. , Usmani Nawaid , Vachon Celine M. , Van Nieuwenhuysen Els , Vega Ana , Aguado-Barrera Miguel Elías , Wang Qin , Webb Penelope M. , Weinberg Clarice R. , Weinstein Stephanie , Weissler Mark C. , Weitzel Jeffrey N. , West Catharine M. L. , White Emily , Whittemore Alice S. , Wichmann H-Erich , Wiklund Fredrik , Winqvist Robert , Wolk Alicja , Woll Penella , Woods Michael , Wu Anna H. , Wu Xifeng , Yannoukakos Drakoulis , Zheng Wei , Zienolddiny Shanbeh , Ziogas Argyrios , Zorn Kristin K. , Lane Jacqueline M. , Saxena Richa , Thomas Duncan , Hung Rayjean J. , Diergaarde Brenda , McKay James , Peters Ulrike , Hsu Li , García-Closas Montserrat , Eeles Rosalind A. , Chenevix-Trench Georgia , Brennan Paul J. , Haiman Christopher A. , Simard Jacques , Easton Douglas F. , Gruber Stephen B. , Pharoah Paul D. P. , Price Alkes L. , Pasaniuc Bogdan , Amos Christopher I. , Kraft Peter , Lindström Sara 
Published: January 2019

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.