Shared heritability and functional enrichment across six solid cancers

Author:

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.,B.M. Claes Kathleen,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.,Velez Edwards Digna R,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,Yun-Hong 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,Kay-Khaw 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,Heinz-Lenz Josef,Leslie Goska,Lessel Davor,Lester Jenny,Levine Douglas A.,Li Li,Li Christopher I.,Lindblom Annika,Lindor Noralane M.,Liu Geoffrey,Loupakis Fotios,Lubinński 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,Al Olama Ali Amin,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 HM.,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,Ruyck Kim De,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.,Nieuwenhuysen Els Van,Vega Ana,Aguado-Barrera Elías Miguel,Wang Qin,Webb Penelope M.,Weinberg Clarice R.,Weinstein Stephanie,Weissler Mark C.,Weitzel Jeffrey N.,West Catharine ML,White Emily,Whittemore Alice S.,H-Wichmann 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.,D.P. Pharoah Paul,Price Alkes L.,Pasaniuc Bogdan,Amos Christopher I.,Kraft Peter,Lindström Sara,

Abstract

ABSTRACTQuantifying 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, 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.

Publisher

Cold Spring Harbor Laboratory

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