Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.
Sampson JN., Wheeler WA., Yeager M., Panagiotou O., Wang Z., Berndt SI., Lan Q., Abnet CC., Amundadottir LT., Figueroa JD., Landi MT., Mirabello L., Savage SA., Taylor PR., De Vivo I., McGlynn KA., Purdue MP., Rajaraman P., Adami H-O., Ahlbom A., Albanes D., Amary MF., An S-J., Andersson U., Andriole G., Andrulis IL., Angelucci E., Ansell SM., Arici C., Armstrong BK., Arslan AA., Austin MA., Baris D., Barkauskas DA., Bassig BA., Becker N., Benavente Y., Benhamou S., Berg C., Van Den Berg D., Bernstein L., Bertrand KA., Birmann BM., Black A., Boeing H., Boffetta P., Boutron-Ruault M-C., Bracci PM., Brinton L., Brooks-Wilson AR., Bueno-de-Mesquita HB., Burdett L., Buring J., Butler MA., Cai Q., Cancel-Tassin G., Canzian F., Carrato A., Carreon T., Carta A., Chan JKC., Chang ET., Chang G-C., Chang I-S., Chang J., Chang-Claude J., Chen C-J., Chen C-Y., Chen C., Chen C-H., Chen C., Chen H., Chen K., Chen K-Y., Chen K-C., Chen Y., Chen Y-H., Chen Y-S., Chen Y-M., Chien L-H., Chirlaque M-D., Choi JE., Choi YY., Chow W-H., Chung CC., Clavel J., Clavel-Chapelon F., Cocco P., Colt JS., Comperat E., Conde L., Connors JM., Conti D., Cortessis VK., Cotterchio M., Cozen W., Crouch S., Crous-Bou M., Cussenot O., Davis FG., Ding T., Diver WR., Dorronsoro M., Dossus L., Duell EJ., Ennas MG., Erickson RL., Feychting M., Flanagan AM., Foretova L., Fraumeni JF., Freedman ND., Beane Freeman LE., Fuchs C., Gago-Dominguez M., Gallinger S., Gao Y-T., Gapstur SM., Garcia-Closas M., García-Closas R., Gascoyne RD., Gastier-Foster J., Gaudet MM., Gaziano JM., Giffen C., Giles GG., Giovannucci E., Glimelius B., Goggins M., Gokgoz N., Goldstein AM., Gorlick R., Gross M., Grubb R., Gu J., Guan P., Gunter M., Guo H., Habermann TM., Haiman CA., Halai D., Hallmans G., Hassan M., Hattinger C., He Q., He X., Helzlsouer K., Henderson B., Henriksson R., Hjalgrim H., Hoffman-Bolton J., Hohensee C., Holford TR., Holly EA., Hong Y-C., Hoover RN., Horn-Ross PL., Hosain GMM., Hosgood HD., Hsiao C-F., Hu N., Hu W., Hu Z., Huang M-S., Huerta J-M., Hung J-Y., Hutchinson A., Inskip PD., Jackson RD., Jacobs EJ., Jenab M., Jeon H-S., Ji B-T., Jin G., Jin L., Johansen C., Johnson A., Jung YJ., Kaaks R., Kamineni A., Kane E., Kang CH., Karagas MR., Kelly RS., Khaw K-T., Kim C., Kim HN., Kim JH., Kim JS., Kim YH., Kim YT., Kim Y-C., Kitahara CM., Klein AP., Klein RJ., Kogevinas M., Kohno T., Kolonel LN., Kooperberg C., Kricker A., Krogh V., Kunitoh H., Kurtz RC., Kweon S-S., LaCroix A., Lawrence C., Lecanda F., Lee VHF., Li D., Li H., Li J., Li Y-J., Li Y., Liao LM., Liebow M., Lightfoot T., Lim W-Y., Lin C-C., Lin D., Lindstrom S., Linet MS., Link BK., Liu C., Liu J., Liu L., Ljungberg B., Lloreta J., Di Lollo S., Lu D., Lund E., Malats N., Mannisto S., Le Marchand L., Marina N., Masala G., Mastrangelo G., Matsuo K., Maynadie M., McKay J., McKean-Cowdin R., Melbye M., Melin BS., Michaud DS., Mitsudomi T., Monnereau A., Montalvan R., Moore LE., Mortensen LM., Nieters A., North KE., Novak AJ., Oberg AL., Offit K., Oh I-J., Olson SH., Palli D., Pao W., Park IK., Park JY., Park KH., Patiño-Garcia A., Pavanello S., Peeters PHM., Perng R-P., Peters U., Petersen GM., Picci P., Pike MC., Porru S., Prescott J., Prokunina-Olsson L., Qian B., Qiao Y-L., Rais M., Riboli E., Riby J., Risch HA., Rizzato C., Rodabough R., Roman E., Roupret M., Ruder AM., Sanjose SD., Scelo G., Schned A., Schumacher F., Schwartz K., Schwenn M., Scotlandi K., Seow A., Serra C., Serra M., Sesso HD., Setiawan VW., Severi G., Severson RK., Shanafelt TD., Shen H., Shen W., Shin M-H., Shiraishi K., Shu X-O., Siddiq A., Sierrasesúmaga L., Sihoe ADL., Skibola CF., Smith A., Smith MT., Southey MC., Spinelli JJ., Staines A., Stampfer M., Stern MC., Stevens VL., Stolzenberg-Solomon RS., Su J., Su W-C., Sund M., Sung JS., Sung SW., Tan W., Tang W., Tardón A., Thomas D., Thompson CA., Tinker LF., Tirabosco R., Tjønneland A., Travis RC., Trichopoulos D., Tsai F-Y., Tsai Y-H., Tucker M., Turner J., Vajdic CM., Vermeulen RCH., Villano DJ., Vineis P., Virtamo J., Visvanathan K., Wactawski-Wende J., Wang C., Wang C-L., Wang J-C., Wang J., Wei F., Weiderpass E., Weiner GJ., Weinstein S., Wentzensen N., White E., Witzig TE., Wolpin BM., Wong MP., Wu C., Wu G., Wu J., Wu T., Wu W., Wu X., Wu Y-L., Wunder JS., Xiang Y-B., Xu J., Xu P., Yang P-C., Yang T-Y., Ye Y., Yin Z., Yokota J., Yoon H-I., Yu C-J., Yu H., Yu K., Yuan J-M., Zelenetz A., Zeleniuch-Jacquotte A., Zhang X-C., Zhang Y., Zhao X., Zhao Z., Zheng H., Zheng T., Zheng W., Zhou B., Zhu M., Zucca M., Boca SM., Cerhan JR., Ferri GM., Hartge P., Hsiung CA., Magnani C., Miligi L., Morton LM., Smedby KE., Teras LR., Vijai J., Wang SS., Brennan P., Caporaso NE., Hunter DJ., Kraft P., Rothman N., Silverman DT., Slager SL., Chanock SJ., Chatterjee N.
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.