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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
Joshua N Sampson1, William A Wheeler1, Meredith Yeager1
1Division 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
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.
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