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1. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Author

Berndt SI, Camp NJ, Skibola CF, Vijai J, Wang Z, Gu J, Nieters A, Kelly RS, Smedby KE, Monnereau A, Cozen W, Cox A, Wang SS, Lan Q, Teras LR, Machado M, Yeager M, Brooks-Wilson AR, Hartge P, Purdue MP, Birmann BM, Vajdic CM, Cocco P, Zhang Y, Giles GG, Zeleniuch-Jacquotte A, Lawrence C, Montalvan R, Burdett L, Hutchinson A, Ye Y, Call TG, Shanafelt TD, Novak AJ, Kay NE, Liebow M, Cunningham JM, Allmer C, Hjalgrim H, Adami HO, Melbye M, Glimelius B, Chang ET, Glenn M, Curtin K, Cannon-Albright LA, Diver WR, Link BK, Weiner GJ, Conde L, Bracci PM, Riby J, Arnett DK, Zhi D, Leach JM, Holly EA, Jackson RD, Tinker LF, Benavente Y, Sala N, Casabonne D, Becker N, Boffetta P, Brennan P, Foretova L, Maynadie M, McKay J, Staines A, Chaffee KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS, Leis JF, Weinberg JB, Caporaso NE, Norman AD, De Roos AJ, Morton LM, Severson RK, Riboli E, Vineis P, Kaaks R, Masala G, Weiderpass E, Chirlaque MD, Vermeulen RCH, Travis RC, Southey MC, Milne RL, Albanes D, Virtamo J, Weinstein S, Clavel J, Zheng T, Holford TR, Villano DJ, Maria A, Spinelli JJ, Gascoyne RD, Connors JM, Bertrand KA, Giovannucci E, Kraft P, Kricker A, Turner J, Ennas MG, Ferri GM, Miligi L, Liang L, Ma B, Huang J, Crouch S, Park JH, Chatterjee N, North KE, Snowden JA, Wright J, Fraumeni JF, Offit K, Wu X, de Sanjose S, Cerhan JR, Chanock SJ, Rothman N, and Slager SL

Subjects
Adaptor Proteins, Signal Transducing genetics, Apoptosis Regulatory Proteins genetics, Bcl-2-Like Protein 11, Genetic Predisposition to Disease, Humans, Membrane Proteins genetics, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins genetics, Serpins genetics, T-Box Domain Proteins genetics, Genome-Wide Association Study, Leukemia, Lymphocytic, Chronic, B-Cell genetics, White People genetics
Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

Published
2016
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2. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

Author

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 HO, Ahlbom A, Albanes D, Amary MF, An SJ, Andersson U, Andriole G Jr, 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 MC, 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 JK, Chang ET, Chang GC, Chang IS, Chang J, Chang-Claude J, Chen CJ, Chen CY, Chen C, Chen CH, Chen C, Chen H, Chen K, Chen KY, Chen KC, Chen Y, Chen YH, Chen YS, Chen YM, Chien LH, Chirlaque MD, Choi JE, Choi YY, Chow WH, 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 Jr, Freedman ND, Beane Freeman LE, Fuchs C, Gago-Dominguez M, Gallinger S, Gao YT, 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 3rd, 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 YC, Hoover RN, Horn-Ross PL, Hosain GM, Hosgood HD 3rd, Hsiao CF, Hu N, Hu W, Hu Z, Huang MS, Huerta JM, Hung JY, Hutchinson A, Inskip PD, Jackson RD, Jacobs EJ, Jenab M, Jeon HS, Ji BT, Jin G, Jin L, Johansen C, Johnson A, Jung YJ, Kaaks R, Kamineni A, Kane E, Kang CH, Karagas MR, Kelly RS, Khaw KT, Kim C, Kim HN, Kim JH, Kim JS, Kim YH, Kim YT, Kim YC, Kitahara CM, Klein AP, Klein RJ, Kogevinas M, Kohno T, Kolonel LN, Kooperberg C, Kricker A, Krogh V, Kunitoh H, Kurtz RC, Kweon SS, LaCroix A, Lawrence C, Lecanda F, Lee VH, Li D, Li H, Li J, Li YJ, Li Y, Liao LM, Liebow M, Lightfoot T, Lim WY, Lin CC, 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 IJ, Olson SH, Palli D, Pao W, Park IK, Park JY, Park KH, Patiño-Garcia A, Pavanello S, Peeters PH, Perng RP, Peters U, Petersen GM, Picci P, Pike MC, Porru S, Prescott J, Prokunina-Olsson L, Qian B, Qiao YL, 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 MH, Shiraishi K, Shu XO, Siddiq A, Sierrasesúmaga L, Sihoe AD, Skibola CF, Smith A, Smith MT, Southey MC, Spinelli JJ, Staines A, Stampfer M, Stern MC, Stevens VL, Stolzenberg-Solomon RS, Su J, Su WC, 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 FY, Tsai YH, Tucker M, Turner J, Vajdic CM, Vermeulen RC, Villano DJ, Vineis P, Virtamo J, Visvanathan K, Wactawski-Wende J, Wang C, Wang CL, Wang JC, 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 YL, Wunder JS, Xiang YB, Xu J, Xu P, Yang PC, Yang TY, Ye Y, Yin Z, Yokota J, Yoon HI, Yu CJ, Yu H, Yu K, Yuan JM, Zelenetz A, Zeleniuch-Jacquotte A, Zhang XC, 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, and Chatterjee N

Subjects
Adult, Aged, Asian People genetics, Asian People statistics & numerical data, Bone Neoplasms genetics, Female, Humans, Kidney Neoplasms genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lung Neoplasms etiology, Lung Neoplasms genetics, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, Neoplasms etiology, Osteosarcoma genetics, Polymorphism, Single Nucleotide, Smoking adverse effects, Testicular Neoplasms genetics, Tissue Array Analysis, Urinary Bladder Neoplasms etiology, Urinary Bladder Neoplasms genetics, White People genetics, White People statistics & numerical data, Genetic Predisposition to Disease, Genome-Wide Association Study, Neoplasms genetics
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., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Published
2015
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3. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.

Author

Skibola CF, Berndt SI, Vijai J, Conde L, Wang Z, Yeager M, de Bakker PI, Birmann BM, Vajdic CM, Foo JN, Bracci PM, Vermeulen RC, Slager SL, de Sanjose S, Wang SS, Linet MS, Salles G, Lan Q, Severi G, Hjalgrim H, Lightfoot T, Melbye M, Gu J, Ghesquières H, Link BK, Morton LM, Holly EA, Smith A, Tinker LF, Teras LR, Kricker A, Becker N, Purdue MP, Spinelli JJ, Zhang Y, Giles GG, Vineis P, Monnereau A, Bertrand KA, Albanes D, Zeleniuch-Jacquotte A, Gabbas A, Chung CC, Burdett L, Hutchinson A, Lawrence C, Montalvan R, Liang L, Huang J, Ma B, Liu J, Adami HO, Glimelius B, Ye Y, Nowakowski GS, Dogan A, Thompson CA, Habermann TM, Novak AJ, Liebow M, Witzig TE, Weiner GJ, Schenk M, Hartge P, De Roos AJ, Cozen W, Zhi D, Akers NK, Riby J, Smith MT, Lacher M, Villano DJ, Maria A, Roman E, Kane E, Jackson RD, North KE, Diver WR, Turner J, Armstrong BK, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, Staines A, McKay J, Brooks-Wilson AR, Zheng T, Holford TR, Chamosa S, Kaaks R, Kelly RS, Ohlsson B, Travis RC, Weiderpass E, Clavel J, Giovannucci E, Kraft P, Virtamo J, Mazza P, Cocco P, Ennas MG, Chiu BC, Fraumeni JF Jr, Nieters A, Offit K, Wu X, Cerhan JR, Smedby KE, Chanock SJ, and Rothman N

Subjects
Alleles, Case-Control Studies, Haplotypes genetics, Humans, Biomarkers, Tumor genetics, Chromosomes, Human genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA Antigens genetics, Lymphoma, Follicular genetics, Polymorphism, Single Nucleotide genetics
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Published
2014
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4. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia.

Author

Berndt SI, Skibola CF, Joseph V, Camp NJ, Nieters A, Wang Z, Cozen W, Monnereau A, Wang SS, Kelly RS, Lan Q, Teras LR, Chatterjee N, Chung CC, Yeager M, Brooks-Wilson AR, Hartge P, Purdue MP, Birmann BM, Armstrong BK, Cocco P, Zhang Y, Severi G, Zeleniuch-Jacquotte A, Lawrence C, Burdette L, Yuenger J, Hutchinson A, Jacobs KB, Call TG, Shanafelt TD, Novak AJ, Kay NE, Liebow M, Wang AH, Smedby KE, Adami HO, Melbye M, Glimelius B, Chang ET, Glenn M, Curtin K, Cannon-Albright LA, Jones B, Diver WR, Link BK, Weiner GJ, Conde L, Bracci PM, Riby J, Holly EA, Smith MT, Jackson RD, Tinker LF, Benavente Y, Becker N, Boffetta P, Brennan P, Foretova L, Maynadie M, McKay J, Staines A, Rabe KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS, Lanasa MC, Spector LG, Leis JF, Cunningham JM, Weinberg JB, Morrison VA, Caporaso NE, Norman AD, Linet MS, De Roos AJ, Morton LM, Severson RK, Riboli E, Vineis P, Kaaks R, Trichopoulos D, Masala G, Weiderpass E, Chirlaque MD, Vermeulen RC, Travis RC, Giles GG, Albanes D, Virtamo J, Weinstein S, Clavel J, Zheng T, Holford TR, Offit K, Zelenetz A, Klein RJ, Spinelli JJ, Bertrand KA, Laden F, Giovannucci E, Kraft P, Kricker A, Turner J, Vajdic CM, Ennas MG, Ferri GM, Miligi L, Liang L, Sampson J, Crouch S, Park JH, North KE, Cox A, Snowden JA, Wright J, Carracedo A, Lopez-Otin C, Bea S, Salaverria I, Martin-Garcia D, Campo E, Fraumeni JF Jr, de Sanjose S, Hjalgrim H, Cerhan JR, Chanock SJ, Rothman N, and Slager SL

Subjects
Case-Control Studies, Chromosomes, Human, Pair 2, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Recombination, Genetic, Risk, Genetic Loci, Genome-Wide Association Study, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

Published
2013
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5. Whole-Genome Sequencing Analysis of Human Metabolome in Multi-Ethnic Populations

Author

Feofanova, Elena V, Brown, Michael R, Alkis, Taryn, Manuel, Astrid M, Li, Xihao, Tahir, Usman A, Li, Zilin, Mendez, Kevin M, Kelly, Rachel S, Qi, Qibin, Chen, Han, Larson, Martin G, Lemaitre, Rozenn N, Morrison, Alanna C, Grieser, Charles, Wong, Kari E, Gersztern, Robert E, Zhao, Zhongming, Lasky-Su, Jessica, and Yu, Bing

Subjects
Genetics, Human Genome, Biotechnology, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Good Health and Well Being, Humans, Quantitative Trait Loci, Ethnicity, Metabolome, Genome-Wide Association Study, Polymorphism, Single Nucleotide, NHLBI Trans-Omics for Precision Medicine
Abstract

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease.

Published
2023

6. A genome-wide association study of marginal zone lymphoma shows association to the HLA region.

Author

Vijai, Joseph, Wang, Zhaoming, Berndt, Sonja I, Skibola, Christine F, Slager, Susan L, de Sanjose, Silvia, Melbye, Mads, Glimelius, Bengt, Bracci, Paige M, Conde, Lucia, Birmann, Brenda M, Wang, Sophia S, Brooks-Wilson, Angela R, Lan, Qing, de Bakker, Paul IW, Vermeulen, Roel CH, Portlock, Carol, Ansell, Stephen M, Link, Brian K, Riby, Jacques, North, Kari E, Gu, Jian, Hjalgrim, Henrik, Cozen, Wendy, Becker, Nikolaus, Teras, Lauren R, Spinelli, John J, Turner, Jenny, Zhang, Yawei, Purdue, Mark P, Giles, Graham G, Kelly, Rachel S, Zeleniuch-Jacquotte, Anne, Ennas, Maria Grazia, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Lightfoot, Tracy, Yeager, Meredith, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Villano, Danylo J, Maria, Ann, Corines, Marina, Thomas, Tinu, Novak, Anne J, Dogan, Ahmet, Liebow, Mark, Thompson, Carrie A, Witzig, Thomas E, Habermann, Thomas M, Weiner, George J, Smith, Martyn T, Holly, Elizabeth A, Jackson, Rebecca D, Tinker, Lesley F, Ye, Yuanqing, Adami, Hans-Olov, Smedby, Karin E, De Roos, Anneclaire J, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Diver, W Ryan, Vajdic, Claire M, Armstrong, Bruce K, Kricker, Anne, Zheng, Tongzhang, Holford, Theodore R, Severi, Gianluca, Vineis, Paolo, Ferri, Giovanni M, Ricco, Rosalia, Miligi, Lucia, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, Virtamo, Jarmo, Smith, Alex, Kane, Eleanor, Roman, Eve, Chiu, Brian CH, Fraumeni, Joseph F, Wu, Xifeng, Cerhan, James R, Offit, Kenneth, and Chanock, Stephen J

Subjects
Humans, Membrane Glycoproteins, Computational Biology, Major Histocompatibility Complex, Genotype, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Lymphoma, B-Cell, Marginal Zone, Genome-Wide Association Study, Butyrophilins, Polymorphism, Single Nucleotide, Lymphoma, B-Cell, Marginal Zone
Abstract

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

Published
2015

7. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

Author

Cerhan, James R, Berndt, Sonja I, Vijai, Joseph, Ghesquières, Hervé, McKay, James, Wang, Sophia S, Wang, Zhaoming, Yeager, Meredith, Conde, Lucia, de Bakker, Paul IW, Nieters, Alexandra, Cox, David, Burdett, Laurie, Monnereau, Alain, Flowers, Christopher R, De Roos, Anneclaire J, Brooks-Wilson, Angela R, Lan, Qing, Severi, Gianluca, Melbye, Mads, Gu, Jian, Jackson, Rebecca D, Kane, Eleanor, Teras, Lauren R, Purdue, Mark P, Vajdic, Claire M, Spinelli, John J, Giles, Graham G, Albanes, Demetrius, Kelly, Rachel S, Zucca, Mariagrazia, Bertrand, Kimberly A, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Hutchinson, Amy, Zhi, Degui, Habermann, Thomas M, Link, Brian K, Novak, Anne J, Dogan, Ahmet, Asmann, Yan W, Liebow, Mark, Thompson, Carrie A, Ansell, Stephen M, Witzig, Thomas E, Weiner, George J, Veron, Amelie S, Zelenika, Diana, Tilly, Hervé, Haioun, Corinne, Molina, Thierry Jo, Hjalgrim, Henrik, Glimelius, Bengt, Adami, Hans-Olov, Bracci, Paige M, Riby, Jacques, Smith, Martyn T, Holly, Elizabeth A, Cozen, Wendy, Hartge, Patricia, Morton, Lindsay M, Severson, Richard K, Tinker, Lesley F, North, Kari E, Becker, Nikolaus, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, Lightfoot, Tracy, Crouch, Simon, Smith, Alex, Roman, Eve, Diver, W Ryan, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Villano, Danylo J, Zheng, Tongzhang, Zhang, Yawei, Holford, Theodore R, Kricker, Anne, Turner, Jenny, Southey, Melissa C, Clavel, Jacqueline, Virtamo, Jarmo, Weinstein, Stephanie, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Vermeulen, Roel CH, Boeing, Heiner, Tjonneland, Anne, Angelucci, Emanuele, Di Lollo, Simonetta, Rais, Marco, and Birmann, Brenda M

Subjects
Human Genome, Rare Diseases, Genetics, Cancer, Hematology, Lymphoma, Aetiology, 2.1 Biological and endogenous factors, Chromosome Mapping, Computational Biology, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Likelihood Functions, Lymphoma, Large B-Cell, Diffuse, Polymorphism, Single Nucleotide, Quantitative Trait Loci, White People, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Published
2014

8. Analysis of heritability and shared heritability based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N., Wheeler, William A., Yeager, Meredith, Panagiotou, Orestis, Wang, Zhaoming, Berndt, Sonja I., Lan, Qing, Abnet, Christian C., Amundadottir, Laufey T., Figueroa, Jonine D., Landi, Maria Teresa, Mirabello, Lisa, Savage, Sharon A., Taylor, Philip R., Vivo, Immaculata De, McGlynn, Katherine A., Purdue, Mark P., Rajaraman, Preetha, Adami, Hans-Olov, Ahlbom, Anders, Albanes, Demetrius, Amary, Maria Fernanda, An, She-Juan, Andersson, Ulrika, Andriole, Gerald, Andrulis, Irene L., Angelucci, Emanuele, Ansell, Stephen M., Arici, Cecilia, Armstrong, Bruce K., Arslan, Alan A., Austin, Melissa A., Baris, Dalsu, Barkauskas, Donald A., Bassig, Bryan A., Becker, Nikolaus, Benavente, Yolanda, Benhamou, Simone, Berg, Christine, Van Den Berg, David, Bernstein, Leslie, Bertrand, Kimberly A., Birmann, Brenda M., Black, Amanda, Boeing, Heiner, Boffetta, Paolo, Boutron-Ruault, Marie-Christine, Bracci, Paige M., Brinton, Louise, Brooks-Wilson, Angela R., Bueno-de-Mesquita, H. Bas, Burdett, Laurie, Buring, Julie, Butler, Mary Ann, Cai, Qiuyin, Cancel-Tassin, Geraldine, Canzian, Federico, Carrato, Alfredo, Carreon, Tania, Carta, Angela, Chan, John K. C., Chang, Ellen T., Chang, Gee-Chen, Chang, I-Shou, Chang, Jiang, Chang-Claude, Jenny, Chen, Chien-Jen, Chen, Chih-Yi, Chen, Chu, Chen, Chung-Hsing, Chen, Constance, Chen, Hongyan, Chen, Kexin, Chen, Kuan-Yu, Chen, Kun-Chieh, Chen, Ying, Chen, Ying-Hsiang, Chen, Yi-Song, Chen, Yuh-Min, Chien, Li-Hsin, Chirlaque, María-Dolores, Choi, Jin Eun, Choi, Yi Young, Chow, Wong-Ho, Chung, Charles C., Clavel, Jacqueline, Clavel-Chapelon, Françoise, Cocco, Pierluigi, Colt, Joanne S., Comperat, Eva, Conde, Lucia, Connors, Joseph M., Conti, David, Cortessis, Victoria K., Cotterchio, Michelle, Cozen, Wendy, Crouch, Simon, Crous-Bou, Marta, Cussenot, Olivier, Davis, Faith G., Ding, Ti, Diver, W. Ryan, Dorronsoro, Miren, Dossus, Laure, Duell, Eric J., Ennas, Maria Grazia, Erickson, Ralph L., Feychting, Maria, Flanagan, Adrienne M., Foretova, Lenka, Fraumeni, Joseph F., Freedman, Neal D., Beane Freeman, Laura E., Fuchs, Charles, Gago-Dominguez, Manuela, Gallinger, Steven, Gao, Yu-Tang, Gapstur, Susan M., Garcia-Closas, Montserrat, García-Closas, Reina, Gascoyne, Randy D., Gastier-Foster, Julie, Gaudet, Mia M., Gaziano, J. Michael, Giffen, Carol, Giles, Graham G., Giovannucci, Edward, Glimelius, Bengt, Goggins, Michael, Gokgoz, Nalan, Goldstein, Alisa M., Gorlick, Richard, Gross, Myron, Grubb, Robert, Gu, Jian, Guan, Peng, Gunter, Marc, Guo, Huan, Habermann, Thomas M., Haiman, Christopher A., Halai, Dina, Hallmans, Goran, Hassan, Manal, Hattinger, Claudia, He, Qincheng, He, Xingzhou, Helzlsouer, Kathy, Henderson, Brian, Henriksson, Roger, Hjalgrim, Henrik, Hoffman-Bolton, Judith, Hohensee, Chancellor, Holford, Theodore R., Holly, Elizabeth A., Hong, Yun-Chul, Hoover, Robert N., Horn-Ross, Pamela L., Hosain, G. M. Monawar, Hosgood, H. Dean, Hsiao, Chin-Fu, Hu, Nan, Hu, Wei, Hu, Zhibin, Huang, Ming-Shyan, Huerta, Jose-Maria, Hung, Jen-Yu, Hutchinson, Amy, Inskip, Peter D., Jackson, Rebecca D., Jacobs, Eric J., Jenab, Mazda, Jeon, Hyo-Sung, Ji, Bu-Tian, Jin, Guangfu, Jin, Li, Johansen, Christoffer, Johnson, Alison, Jung, Yoo Jin, Kaaks, Rudolph, Kamineni, Aruna, Kane, Eleanor, Kang, Chang Hyun, Karagas, Margaret R., Kelly, Rachel S., Khaw, Kay-Tee, Kim, Christopher, Kim, Hee Nam, Kim, Jin Hee, Kim, Jun Suk, Kim, Yeul Hong, Kim, Young Tae, Kim, Young-Chul, Kitahara, Cari M., Klein, Alison P., Klein, Robert J., Kogevinas, Manolis, Kohno, Takashi, Kolonel, Laurence N., Kooperberg, Charles, Kricker, Anne, Krogh, Vittorio, Kunitoh, Hideo, Kurtz, Robert C., Kweon, Sun-Seog, LaCroix, Andrea, Lawrence, Charles, Lecanda, Fernando, Lee, Victor Ho Fun, Li, Donghui, Li, Haixin, Li, Jihua, Li, Yao-Jen, Li, Yuqing, Liao, Linda M., Liebow, Mark, Lightfoot, Tracy, Lim, Wei-Yen, Lin, Chien-Chung, Lin, Dongxin, Lindstrom, Sara, Linet, Martha S., Link, Brian K., Liu, Chenwei, Liu, Jianjun, Liu, Li, Ljungberg, Börje, Lloreta, Josep, Lollo, Simonetta Di, Lu, Daru, Lund, Eiluv, Malats, Nuria, Mannisto, Satu, Marchand, Loic Le, Marina, Neyssa, Masala, Giovanna, Mastrangelo, Giuseppe, Matsuo, Keitaro, Maynadie, Marc, McKay, James, McKean-Cowdin, Roberta, Melbye, Mads, Melin, Beatrice S., Michaud, Dominique S., Mitsudomi, Tetsuya, Monnereau, Alain, Montalvan, Rebecca, Moore, Lee E., Mortensen, Lotte Maxild, Nieters, Alexandra, North, Kari E., Novak, Anne J., Oberg, Ann L., Offit, Kenneth, Oh, In-Jae, Olson, Sara H., Palli, Domenico, Pao, William, Park, In Kyu, Park, Jae Yong, Park, Kyong Hwa, Patiño-Garcia, Ana, Pavanello, Sofia, Peeters, Petra H. M., Perng, Reury-Perng, Peters, Ulrike, Petersen, Gloria M., Picci, Piero, Pike, Malcolm C., Porru, Stefano, Prescott, Jennifer, Prokunina-Olsson, Ludmila, Qian, Biyun, Qiao, You-Lin, Rais, Marco, Riboli, Elio, Riby, Jacques, Risch, Harvey A., Rizzato, Cosmeri, Rodabough, Rebecca, Roman, Eve, Roupret, Morgan, Ruder, Avima M., de Sanjose, Silvia, Scelo, Ghislaine, Schned, Alan, Schumacher, Fredrick, Schwartz, Kendra, Schwenn, Molly, Scotlandi, Katia, Seow, Adeline, Serra, Consol, Serra, Massimo, Sesso, Howard D., Setiawan, Veronica Wendy, Severi, Gianluca, Severson, Richard K., Shanafelt, Tait D., Shen, Hongbing, Shen, Wei, Shin, Min-Ho, Shiraishi, Kouya, Shu, Xiao-Ou, Siddiq, Afshan, Sierrasesúmaga, Luis, Sihoe, Alan Dart Loon, Skibola, Christine F., Smith, Alex, Smith, Martyn T., Southey, Melissa C., Spinelli, John J., Staines, Anthony, Stampfer, Meir, Stern, Marianna C., Stevens, Victoria L., Stolzenberg-Solomon, Rachael S., Su, Jian, Su, Wu-Chou, Sund, Malin, Sung, Jae Sook, Sung, Sook Whan, Tan, Wen, Tang, Wei, Tardón, Adonina, Thomas, David, Thompson, Carrie A., Tinker, Lesley F., Tirabosco, Roberto, Tjønneland, Anne, Travis, Ruth C., Trichopoulos, Dimitrios, Tsai, Fang-Yu, Tsai, Ying-Huang, Tucker, Margaret, Turner, Jenny, Vajdic, Claire M., Vermeulen, Roel C. H., Villano, Danylo J., Vineis, Paolo, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chaoyu, Wang, Chih-Liang, Wang, Jiu-Cun, Wang, Junwen, Wei, Fusheng, Weiderpass, Elisabete, Weiner, George J., Weinstein, Stephanie, Wentzensen, Nicolas, White, Emily, Witzig, Thomas E., Wolpin, Brian M., Wong, Maria Pik, Wu, Chen, Wu, Guoping, Wu, Junjie, Wu, Tangchun, Wu, Wei, Wu, Xifeng, Wu, Yi-Long, Wunder, Jay S., Xiang, Yong-Bing, Xu, Jun, Xu, Ping, Yang, Pan-Chyr, Yang, Tsung-Ying, Ye, Yuanqing, Yin, Zhihua, Yokota, Jun, Yoon, Ho-Il, Yu, Chong-Jen, Yu, Herbert, Yu, Kai, Yuan, Jian-Min, Zelenetz, Andrew, Zeleniuch-Jacquotte, Anne, Zhang, Xu-Chao, Zhang, Yawei, Zhao, Xueying, Zhao, Zhenhong, Zheng, Hong, Zheng, Tongzhang, Zheng, Wei, Zhou, Baosen, Zhu, Meng, Zucca, Mariagrazia, Boca, Simina M., Cerhan, James R., Ferri, Giovanni M., Hartge, Patricia, Hsiung, Chao Agnes, Magnani, Corrado, Miligi, Lucia, Morton, Lindsay M., Smedby, Karin E., Teras, Lauren R., Vijai, Joseph, Wang, Sophia S., Brennan, Paul, Caporaso, Neil E., Hunter, David J., Kraft, Peter, Rothman, Nathaniel, Silverman, Debra T., Slager, Susan L., Chanock, Stephen J., and Chatterjee, Nilanjan

Subjects
Adult, Asian Continental Ancestry Group, Male, Lung Neoplasms, DATABASE, European Continental Ancestry Group, RELATIVES, Bone Neoplasms, Polymorphism, Single Nucleotide, Article, LUNG-CANCER, Testicular Neoplasms, Neoplasms, SWEDEN, LYMPHOMA, Humans, Genetic Predisposition to Disease, FAMILIAL RISK, Oncology & Carcinogenesis, Aged, Osteosarcoma, Science & Technology, MUTATIONS, Smoking, Middle Aged, Leukemia, Lymphocytic, Chronic, B-Cell, PANCREATIC-CANCER, Kidney Neoplasms, MULTIPLE SUSCEPTIBILITY LOCI, INDIVIDUALS, Oncology, Urinary Bladder Neoplasms, Tissue Array Analysis, Female, Lymphoma, Large B-Cell, Diffuse, Life Sciences & Biomedicine, 1112 Oncology And Carcinogenesis, Genome-Wide Association Study
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 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 cases and 34,131 controls. 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, hl2, 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% CI = 14% - 37%) and 7% (4% - 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 non-smoking 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.

Published
2015

9. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author

Skibola, Christine F, Berndt, Sonja I, Vijai, Joseph, Conde, Lucia, Wang, Zhaoming, Yeager, Meredith, de Bakker, Paul IW, Birmann, Brenda M, Vajdic, Claire M, Foo, Jia-Nee, Bracci, Paige M, Vermeulen, Roel CH, Slager, Susan L, de Sanjose, Silvia, Wang, Sophia S, Linet, Martha S, Salles, Gilles, Lan, Qing, Severi, Gianluca, Hjalgrim, Henrik, Lightfoot, Tracy, Melbye, Mads, Gu, Jian, Ghesquières, Hervé, Link, Brian K, Morton, Lindsay M, Holly, Elizabeth A, Smith, Alex, Tinker, Lesley F, Teras, Lauren R, Kricker, Anne, Becker, Nikolaus, Purdue, Mark P, Spinelli, John J, Zhang, Yawei, Giles, Graham G, Vineis, Paolo, Monnereau, Alain, Bertrand, Kimberly A, Albanes, Demetrius, Zeleniuch-Jacquotte, Anne, Gabbas, Attilio, Chung, Charles C, Burdett, Laurie, Hutchinson, Amy, Lawrence, Charles, Montalvan, Rebecca, Liang, Liming, Huang, Jinyan, Ma, Baoshan, Liu, Jianjun, Adami, Hans-Olov, Glimelius, Bengt, Ye, Yuanqing, Nowakowski, Grzegorz S, Dogan, Ahmet, Thompson, Carrie A, Habermann, Thomas M, Novak, Anne J, Liebow, Mark, Witzig, Thomas E, Weiner, George J, Schenk, Maryjean, Hartge, Patricia, De Roos, Anneclaire J, Cozen, Wendy, Zhi, Degui, Akers, Nicholas K, Riby, Jacques, Smith, Martyn T, Lacher, Mortimer, Villano, Danylo J, Maria, Ann, Roman, Eve, Kane, Eleanor, Jackson, Rebecca D, North, Kari E, Diver, W Ryan, Turner, Jenny, Armstrong, Bruce K, Benavente, Yolanda, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Staines, Anthony, McKay, James, Brooks-Wilson, Angela R, Zheng, Tongzhang, Holford, Theodore R, Chamosa, Saioa, Kaaks, Rudolph, Kelly, Rachel S, Ohlsson, Bodil, Travis, Ruth C, Weiderpass, Elisabete, Clavel, Jacqueline, Giovannucci, Edward, Kraft, Peter, and Virtamo, Jarmo

Subjects
Lymphoma, Medical and Health Sciences, Chromosomes, Rare Diseases, HLA Antigens, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Polymorphism, Aetiology, Alleles, Cancer, Genetics & Heredity, Tumor, Human Genome, Follicular, Single Nucleotide, Hematology, Biological Sciences, Haplotypes, Case-Control Studies, Biomarkers, Human, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Published
2014

10. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia

Author

Berndt, Sonja I, Skibola, Christine F, Joseph, Vijai, Camp, Nicola J, Nieters, Alexandra, Wang, Zhaoming, Cozen, Wendy, Monnereau, Alain, Wang, Sophia S, Kelly, Rachel S, Lan, Qing, Teras, Lauren R, Chatterjee, Nilanjan, Chung, Charles C, Yeager, Meredith, Brooks-Wilson, Angela R, Hartge, Patricia, Purdue, Mark P, Birmann, Brenda M, Armstrong, Bruce K, Cocco, Pierluigi, Zhang, Yawei, Severi, Gianluca, Zeleniuch-Jacquotte, Anne, Lawrence, Charles, Burdette, Laurie, Yuenger, Jeffrey, Hutchinson, Amy, Jacobs, Kevin B, Call, Timothy G, Shanafelt, Tait D, Novak, Anne J, Kay, Neil E, Liebow, Mark, Wang, Alice H, Smedby, Karin E, Adami, Hans-Olov, Melbye, Mads, Glimelius, Bengt, Chang, Ellen T, Glenn, Martha, Curtin, Karen, Cannon-Albright, Lisa A, Jones, Brandt, Diver, W Ryan, Link, Brian K, Weiner, George J, Conde, Lucia, Bracci, Paige M, Riby, Jacques, Holly, Elizabeth A, Smith, Martyn T, Jackson, Rebecca D, Tinker, Lesley F, Benavente, Yolanda, Becker, Nikolaus, Boffetta, Paolo, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, McKay, James, Staines, Anthony, Rabe, Kari G, Achenbach, Sara J, Vachon, Celine M, Goldin, Lynn R, Strom, Sara S, Lanasa, Mark C, Spector, Logan G, Leis, Jose F, Cunningham, Julie M, Weinberg, J Brice, Morrison, Vicki A, Caporaso, Neil E, Norman, Aaron D, Linet, Martha S, De Roos, Anneclaire J, Morton, Lindsay M, Severson, Richard K, Riboli, Elio, Vineis, Paolo, Kaaks, Rudolph, Trichopoulos, Dimitrios, Masala, Giovanna, Weiderpass, Elisabete, Chirlaque, María-Dolores, Vermeulen, Roel CH, Travis, Ruth C, Giles, Graham G, Albanes, Demetrius, Virtamo, Jarmo, Weinstein, Stephanie, Clavel, Jacqueline, Zheng, Tongzhang, Holford, Theodore R, Offit, Kenneth, Zelenetz, Andrew, Klein, Robert J, Spinelli, John J, and Bertrand, Kimberly A

Subjects
Risk, Leukemia, B-Cell, Single Nucleotide, Biological Sciences, Medical and Health Sciences, Chromosomes, Recombination, Linkage Disequilibrium, Lymphocytic, Genetic, Genetic Loci, Case-Control Studies, Pair 2, Humans, Genetic Predisposition to Disease, Polymorphism, Chronic, Human, Genome-Wide Association Study, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

Published
2013

11. Life-course socioeconomic status and DNA methylation of genes regulating inflammation

Author

Paolo Vineis, Domenico Palli, Maria Concetta Giurdanella, Fred Paccaud, Raphaële Castagné, Giovanna Masala, Gianluca Campanella, Marc Chadeau-Hyam, Amalia Mattiello, Salvatore Panico, Silvia Stringhini, Rachel S. Kelly, Rosario Tumino, Carlotta Sacerdote, Karin van Veldhoven, Sara Grioni, Claudia Agnoli, Silvia Polidoro, Valentina Gallo, Campanella G., Stringhini, Silvia, Polidoro, Silvia, Sacerdote, Carlotta, Kelly, Rachel S, van Veldhoven, Karin, Agnoli, Claudia, Grioni, Sara, Tumino, Rosario, Giurdanella, Maria Concetta, Panico, Salvatore, Mattiello, Amalia, Palli, Domenico, Masala, Giovanna, Gallo, Valentina, Castagné, Raphaële, Paccaud, Fred, Campanella, Gianluca, Chadeau Hyam, Marc, and Vineis, Paolo

Subjects
Male, Candidate gene, Epidemiology, Context (language use), Genome-wide association study, Biology, Social Environment, NFATC Transcription Factor, 03 medical and health sciences, 0302 clinical medicine, Inflammation/genetics, Humans, Prospective Studies, 030212 general & internal medicine, Epigenetics, NFATC Transcription Factors/genetics, Multivariate Analysi, Gene, 030304 developmental biology, life course, Inflammation, 0303 health sciences, DNA methylation, NFATC Transcription Factors, social sciences, General Medicine, Methylation, DNA Methylation, Middle Aged, Healthy Volunteer, Healthy Volunteers, 3. Good health, Prospective Studie, Italy, Social Class, IL1A, socioeconomic statu, Multivariate Analysis, Immunology, Female, Genome-Wide Association Study, Human
Abstract

BACKGROUND: In humans, low socioeconomic status (SES) across the life course is associated with greater diurnal cortisol production, increased inflammatory activity and higher circulating antibodies for several pathogens, all suggesting a dampened immune response. Recent evidence suggests that DNA methylation of pro-inflammatory genes may be implicated in the biological embedding of the social environment. METHODS: The present study examines the association between life-course SES and DNA methylation of candidate genes, selected on the basis of their involvement in SES-related inflammation, in the context of a genome-wide methylation study. Participants were 857 healthy individuals sampled from the EPIC Italy prospective cohort study. RESULTS: Indicators of SES were associated with DNA methylation of genes involved in inflammation. NFATC1, in particular, was consistently found to be less methylated in individuals with low vs high SES, in a dose-dependent manner. IL1A, GPR132 and genes belonging to the MAPK family were also less methylated among individuals with low SES. In addition, associations were found between SES and CXCL2 and PTGS2, but these genes were consistently more methylated among low SES individuals. CONCLUSIONS: Our findings support the hypothesis that the social environment leaves an epigenetic signature in cells. Although the functional significance of SES-related DNA methylation is still unclear, we hypothesize that it may link SES to chronic disease risk.

Published
2015
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