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J Natl Cancer Inst. 2015 Oct 12;107(12):djv279. doi: 10.1093/jnci/djv279. Print 2015 Dec.

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

Sampson JN1, Wheeler WA1, Yeager M1, Panagiotou O1, Wang Z1, Berndt SI1, Lan Q1, Abnet CC1, Amundadottir LT1, Figueroa JD1, Landi MT1, Mirabello L1, Savage SA1, Taylor PR1, De Vivo I1, McGlynn KA1, Purdue MP1, Rajaraman P1, Adami HO1, Ahlbom A1, Albanes D1, Amary MF1, An SJ1, Andersson U1, Andriole G Jr1, Andrulis IL1, Angelucci E1, Ansell SM1, Arici C1, Armstrong BK1, Arslan AA1, Austin MA1, Baris D1, Barkauskas DA1, Bassig BA1, Becker N1, Benavente Y1, Benhamou S1, Berg C1, Van Den Berg D1, Bernstein L1, Bertrand KA1, Birmann BM1, Black A1, Boeing H1, Boffetta P1, Boutron-Ruault MC1, Bracci PM1, Brinton L1, Brooks-Wilson AR1, Bueno-de-Mesquita HB1, Burdett L1, Buring J1, Butler MA1, Cai Q1, Cancel-Tassin G1, Canzian F1, Carrato A1, Carreon T1, Carta A1, Chan JK1, Chang ET1, Chang GC1, Chang IS1, Chang J1, Chang-Claude J1, Chen CJ1, Chen CY1, Chen C1, Chen CH1, Chen C1, Chen H1, Chen K1, Chen KY1, Chen KC1, Chen Y1, Chen YH1, Chen YS1, Chen YM1, Chien LH1, Chirlaque MD1, Choi JE1, Choi YY1, Chow WH1, Chung CC1, Clavel J1, Clavel-Chapelon F1, Cocco P1, Colt JS1, Comperat E1, Conde L1, Connors JM1, Conti D1, Cortessis VK1, Cotterchio M1, Cozen W1, Crouch S1, Crous-Bou M1, Cussenot O1, Davis FG1, Ding T1, Diver WR1, Dorronsoro M1, Dossus L1, Duell EJ1, Ennas MG1, Erickson RL1, Feychting M1, Flanagan AM1, Foretova L1, Fraumeni JF Jr1, Freedman ND1, Beane Freeman LE1, Fuchs C1, Gago-Dominguez M1, Gallinger S1, Gao YT1, Gapstur SM1, Garcia-Closas M1, García-Closas R1, Gascoyne RD1, Gastier-Foster J1, Gaudet MM1, Gaziano JM1, Giffen C1, Giles GG1, Giovannucci E1, Glimelius B1, Goggins M1, Gokgoz N1, Goldstein AM1, Gorlick R1, Gross M1, Grubb R 3rd1, Gu J1, Guan P1, Gunter M1, Guo H1, Habermann TM1, Haiman CA1, Halai D1, Hallmans G1, Hassan M1, Hattinger C1, He Q1, He X1, Helzlsouer K1, Henderson B1, Henriksson R1, Hjalgrim H1, Hoffman-Bolton J1, Hohensee C1, Holford TR1, Holly EA1, Hong YC1, Hoover RN1, Horn-Ross PL1, Hosain GM1, Hosgood HD 3rd1, Hsiao CF1, Hu N1, Hu W1, Hu Z1, Huang MS1, Huerta JM1, Hung JY1, Hutchinson A1, Inskip PD1, Jackson RD1, Jacobs EJ1, Jenab M1, Jeon HS1, Ji BT1, Jin G1, Jin L1, Johansen C1, Johnson A1, Jung YJ1, Kaaks R1, Kamineni A1, Kane E1, Kang CH1, Karagas MR1, Kelly RS1, Khaw KT1, Kim C1, Kim HN1, Kim JH1, Kim JS1, Kim YH1, Kim YT1, Kim YC1, Kitahara CM1, Klein AP1, Klein RJ1, Kogevinas M1, Kohno T1, Kolonel LN1, Kooperberg C1, Kricker A1, Krogh V1, Kunitoh H1, Kurtz RC1, Kweon SS1, LaCroix A1, Lawrence C1, Lecanda F1, Lee VH1, Li D1, Li H1, Li J1, Li YJ1, Li Y1, Liao LM1, Liebow M1, Lightfoot T1, Lim WY1, Lin CC1, Lin D1, Lindstrom S1, Linet MS1, Link BK1, Liu C1, Liu J1, Liu L1, Ljungberg B1, Lloreta J1, Di Lollo S1, Lu D1, Lund E1, Malats N1, Mannisto S1, Le Marchand L1, Marina N1, Masala G1, Mastrangelo G1, Matsuo K1, Maynadie M1, McKay J1, McKean-Cowdin R1, Melbye M1, Melin BS1, Michaud DS1, Mitsudomi T1, Monnereau A1, Montalvan R1, Moore LE1, Mortensen LM1, Nieters A1, North KE1, Novak AJ1, Oberg AL1, Offit K1, Oh IJ1, Olson SH1, Palli D1, Pao W1, Park IK1, Park JY1, Park KH1, Patiño-Garcia A1, Pavanello S1, Peeters PH1, Perng RP1, Peters U1, Petersen GM1, Picci P1, Pike MC1, Porru S1, Prescott J1, Prokunina-Olsson L1, Qian B1, Qiao YL1, Rais M1, Riboli E1, Riby J1, Risch HA1, Rizzato C1, Rodabough R1, Roman E1, Roupret M1, Ruder AM1, Sanjose Sd1, Scelo G1, Schned A1, Schumacher F1, Schwartz K1, Schwenn M1, Scotlandi K1, Seow A1, Serra C1, Serra M1, Sesso HD1, Setiawan VW1, Severi G1, Severson RK1, Shanafelt TD1, Shen H1, Shen W1, Shin MH1, Shiraishi K1, Shu XO1, Siddiq A1, Sierrasesúmaga L1, Sihoe AD1, Skibola CF1, Smith A1, Smith MT1, Southey MC1, Spinelli JJ1, Staines A1, Stampfer M1, Stern MC1, Stevens VL1, Stolzenberg-Solomon RS1, Su J1, Su WC1, Sund M1, Sung JS1, Sung SW1, Tan W1, Tang W1, Tardón A1, Thomas D1, Thompson CA1, Tinker LF1, Tirabosco R1, Tjønneland A1, Travis RC1, Trichopoulos D1, Tsai FY1, Tsai YH1, Tucker M1, Turner J1, Vajdic CM1, Vermeulen RC1, Villano DJ1, Vineis P1, Virtamo J1, Visvanathan K1, Wactawski-Wende J1, Wang C1, Wang CL1, Wang JC1, Wang J1, Wei F1, Weiderpass E1, Weiner GJ1, Weinstein S1, Wentzensen N1, White E1, Witzig TE1, Wolpin BM1, Wong MP1, Wu C1, Wu G1, Wu J1, Wu T1, Wu W1, Wu X1, Wu YL1, Wunder JS1, Xiang YB1, Xu J1, Xu P1, Yang PC1, Yang TY1, Ye Y1, Yin Z1, Yokota J1, Yoon HI1, Yu CJ1, Yu H1, Yu K1, Yuan JM1, Zelenetz A1, Zeleniuch-Jacquotte A1, Zhang XC1, Zhang Y1, Zhao X1, Zhao Z1, Zheng H1, Zheng T1, Zheng W1, Zhou B1, Zhu M1, Zucca M1, Boca SM1, Cerhan JR1, Ferri GM1, Hartge P1, Hsiung CA1, Magnani C1, Miligi L1, Morton LM1, Smedby KE1, Teras LR1, Vijai J1, Wang SS1, Brennan P1, Caporaso NE1, Hunter DJ1, Kraft P1, Rothman N1, Silverman DT1, Slager SL1, Chanock SJ1, Chatterjee N1.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JNS, OP, SIB, QL, CCA, LTA, JDF, MTL, LM, SAS, PRT, KAM, PR, DA, DB, BAB, AB, LBr, WHC, CCC, JSC, JFFJr, NDF, LEBF, MGC, AMG, RNH, NH, WH, PDI, BTJ, CK, CMK, LML, MSL, LEM, LPO, RSSS, WeiT, MT, CWa, SW, NW, KY, PH, LMM, NEC, NR, DTS, SJC, NC); Information Management Services, Silver Spring, MD (WAW, CG); Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD (MY, ZW, LBu, AH, CLi); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (IDV, KAB, BMB, CoC, MCB, CF, EG, SL, JP, MSt, DJH); Department of Epidemiology, Harvard School of Public Health, Boston, MA (IDV, OA, KAB, CoC, MCB, EG, RSK, SL, JP, HDS, MSt, DTr, DJH, PK); Ontario Health Study, Toronto, Ontario, Canada (MPP); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (HOA, EWe); Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (AA, MF); UCL Cancer Institute, London, UK (MFA, AMF, DH); Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, UK (MFA, AMF, DH, RT); Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (SJA, JS, YLW, XCZ); Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden (UA, RH, BSM); Division of Urologic Surgery, Washington University School of Medicine, Saint Louis, MO (GAJr, RGIII); Litwin Centre for Cancer Genetics, University of Toronto, Ontario, Canada (ILA, NG, JSW); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA, SG, NG, JSW); Hematology Unit, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari, Italy (EA); Department of Medicin

Erratum in

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

PMID:
26464424
PMCID:
PMC4806328
DOI:
10.1093/jnci/djv279
[Indexed for MEDLINE]
Free PMC Article

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