Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Sonja I. Berndt; Joseph Vijai; Yolanda Benavente; Nicola J. Camp; Alexandra Nieters; Zhaoming Wang; Karin E. Smedby; Geffen Kleinstern; Henrik Hjalgrim; Caroline Besson; Christine F. Skibola; Lindsay M. Morton; Angela R. Brooks-Wilson; Lauren R. Teras; Charles Breeze; Joshua Arias; Hans Olov Adami; Demetrius Albanes; Kenneth C. Anderson; Stephen M. Ansell; Bryan Bassig; Nikolaus Becker; Parveen Bhatti; Brenda M. Birmann; Paolo Boffetta; Paige M. Bracci; Paul Brennan; Elizabeth E. Brown; Laurie Burdett; Lisa A. Cannon-Albright; Ellen T. Chang; Brian C.H. Chiu; Charles C. Chung; Jacqueline Clavel; Pierluigi Cocco; Graham Colditz; Lucia Conde; David V. Conti; David G. Cox; Karen Curtin; Delphine Casabonne; Immaculata De Vivo; W. Ryan Diver; Ahmet Dogan; Christopher K. Edlund; Lenka Foretova; Joseph F. Fraumeni; Attilio Gabbas; Hervé Ghesquières; Graham G. Giles; Sally Glaser; Martha Glenn; Bengt Glimelius; Jian Gu; Thomas M. Habermann; Christopher A. Haiman; Corinne Haioun; Jonathan N. Hofmann; Theodore R. Holford; Elizabeth A. Holly; Amy Hutchinson; Aalin Izhar; Rebecca D. Jackson; Ruth F. Jarrett; Rudolph Kaaks; Eleanor Kane; Laurence N. Kolonel; Yinfei Kong; Peter Kraft; Anne Kricker; Annette Lake; Qing Lan; Charles Lawrence; Dalin Li; Mark Liebow; Brian K. Link; Corrado Magnani; Marc Maynadie; James McKay; Mads Melbye; Lucia Miligi; Roger L. Milne; Thierry J. Molina; Alain Monnereau; Rebecca Montalvan; Kari E. North; Anne J. Novak; Kenan Onel; Mark P. Purdue; Kristin A. Rand; Elio Riboli; Jacques Riby; Eve Roman; Gilles Salles; Douglas W. Sborov; Richard K. Severson; Tait D. Shanafelt; Martyn T. Smith; Alexandra Smith; Kevin W. Song; Lei Song; Melissa C. Southey; John J. Spinelli; Anthony Staines; Deborah Stephens; Heather J. Sutherland; Kaitlyn Tkachuk; Carrie A. Thompson; Hervé Tilly; Lesley F. Tinker; Ruth C. Travis; Jenny Turner; Celine M. Vachon; Claire M. Vajdic; Anke Van Den Berg; David J. Van Den Berg; Roel C.H. Vermeulen; Paolo Vineis; Sophia S. Wang; Elisabete Weiderpass; George J. Weiner; Stephanie Weinstein; Nicole Wong Doo; Yuanqing Ye; Meredith Yeager; Kai Yu; Anne Zeleniuch-Jacquotte; Yawei Zhang; Tongzhang Zheng; Elad Ziv; Joshua Sampson; Nilanjan Chatterjee; Kenneth Offit; Wendy Cozen; Xifeng Wu; James R. Cerhan; Stephen J. Chanock; Susan L. Slager; Nathaniel Rothman

doi:10.1038/s41375-022-01711-0

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

Sonja I. Berndt, Joseph Vijai, Yolanda Benavente, Nicola J. Camp, Alexandra Nieters, Zhaoming Wang, Karin E. Smedby, Geffen Kleinstern, Henrik Hjalgrim, Caroline Besson, Christine F. Skibola, Lindsay M. Morton, Angela R. Brooks-Wilson, Lauren R. Teras, Charles Breeze, Joshua Arias, Hans Olov Adami, Demetrius Albanes, Kenneth C. Anderson, Stephen M. AnsellBryan Bassig, Nikolaus Becker, Parveen Bhatti, Brenda M. Birmann, Paolo Boffetta, Paige M. Bracci, Paul Brennan, Elizabeth E. Brown, Laurie Burdett, Lisa A. Cannon-Albright, Ellen T. Chang, Brian C.H. Chiu, Charles C. Chung, Jacqueline Clavel, Pierluigi Cocco, Graham Colditz, Lucia Conde, David V. Conti, David G. Cox, Karen Curtin, Delphine Casabonne, Immaculata De Vivo, W. Ryan Diver, Ahmet Dogan, Christopher K. Edlund, Lenka Foretova, Joseph F. Fraumeni, Attilio Gabbas, Hervé Ghesquières, Graham G. Giles, Sally Glaser, Martha Glenn, Bengt Glimelius, Jian Gu, Thomas M. Habermann, Christopher A. Haiman, Corinne Haioun, Jonathan N. Hofmann, Theodore R. Holford, Elizabeth A. Holly, Amy Hutchinson, Aalin Izhar, Rebecca D. Jackson, Ruth F. Jarrett, Rudolph Kaaks, Eleanor Kane, Laurence N. Kolonel, Yinfei Kong, Peter Kraft, Anne Kricker, Annette Lake, Qing Lan, Charles Lawrence, Dalin Li, Mark Liebow, Brian K. Link, Corrado Magnani, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Alain Monnereau, Rebecca Montalvan, Kari E. North, Anne J. Novak, Kenan Onel, Mark P. Purdue, Kristin A. Rand, Elio Riboli, Jacques Riby, Eve Roman, Gilles Salles, Douglas W. Sborov, Richard K. Severson, Tait D. Shanafelt, Martyn T. Smith, Alexandra Smith, Kevin W. Song, Lei Song, Melissa C. Southey, John J. Spinelli, Anthony Staines, Deborah Stephens, Heather J. Sutherland, Kaitlyn Tkachuk, Carrie A. Thompson, Hervé Tilly, Lesley F. Tinker, Ruth C. Travis, Jenny Turner, Celine M. Vachon, Claire M. Vajdic, Anke Van Den Berg, David J. Van Den Berg, Roel C.H. Vermeulen, Paolo Vineis, Sophia S. Wang, Elisabete Weiderpass, George J. Weiner, Stephanie Weinstein, Nicole Wong Doo, Yuanqing Ye, Meredith Yeager, Kai Yu, Anne Zeleniuch-Jacquotte, Yawei Zhang, Tongzhang Zheng, Elad Ziv, Joshua Sampson, Nilanjan Chatterjee, Kenneth Offit, Wendy Cozen, Xifeng Wu, James R. Cerhan, Stephen J. Chanock, Susan L. Slager, Nathaniel Rothman

Medicine Monash Health

Research output: Contribution to journal › Article › Research › peer-review

2 Citations (Scopus)

Abstract

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10⁻⁸) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10⁻⁹). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10⁻⁸), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Original language	English
Pages (from-to)	2835–2844
Number of pages	12
Journal	Leukemia
Volume	36
DOIs	https://doi.org/10.1038/s41375-022-01711-0
Publication status	Published - Dec 2022

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Berndt, S. I., Vijai, J., Benavente, Y., Camp, N. J., Nieters, A., Wang, Z., Smedby, K. E., Kleinstern, G., Hjalgrim, H., Besson, C., Skibola, C. F., Morton, L. M., Brooks-Wilson, A. R., Teras, L. R., Breeze, C., Arias, J., Adami, H. O., Albanes, D., Anderson, K. C., ... Rothman, N. (2022). Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes. Leukemia, 36, 2835–2844. https://doi.org/10.1038/s41375-022-01711-0

@article{390029be73e94c2da6110324be27cd18,

title = "Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes",

abstract = "Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.",

author = "Berndt, {Sonja I.} and Joseph Vijai and Yolanda Benavente and Camp, {Nicola J.} and Alexandra Nieters and Zhaoming Wang and Smedby, {Karin E.} and Geffen Kleinstern and Henrik Hjalgrim and Caroline Besson and Skibola, {Christine F.} and Morton, {Lindsay M.} and Brooks-Wilson, {Angela R.} and Teras, {Lauren R.} and Charles Breeze and Joshua Arias and Adami, {Hans Olov} and Demetrius Albanes and Anderson, {Kenneth C.} and Ansell, {Stephen M.} and Bryan Bassig and Nikolaus Becker and Parveen Bhatti and Birmann, {Brenda M.} and Paolo Boffetta and Bracci, {Paige M.} and Paul Brennan and Brown, {Elizabeth E.} and Laurie Burdett and Cannon-Albright, {Lisa A.} and Chang, {Ellen T.} and Chiu, {Brian C.H.} and Chung, {Charles C.} and Jacqueline Clavel and Pierluigi Cocco and Graham Colditz and Lucia Conde and Conti, {David V.} and Cox, {David G.} and Karen Curtin and Delphine Casabonne and {De Vivo}, Immaculata and Diver, {W. Ryan} and Ahmet Dogan and Edlund, {Christopher K.} and Lenka Foretova and Fraumeni, {Joseph F.} and Attilio Gabbas and Herv{\'e} Ghesqui{\`e}res and Giles, {Graham G.} and Sally Glaser and Martha Glenn and Bengt Glimelius and Jian Gu and Habermann, {Thomas M.} and Haiman, {Christopher A.} and Corinne Haioun and Hofmann, {Jonathan N.} and Holford, {Theodore R.} and Holly, {Elizabeth A.} and Amy Hutchinson and Aalin Izhar and Jackson, {Rebecca D.} and Jarrett, {Ruth F.} and Rudolph Kaaks and Eleanor Kane and Kolonel, {Laurence N.} and Yinfei Kong and Peter Kraft and Anne Kricker and Annette Lake and Qing Lan and Charles Lawrence and Dalin Li and Mark Liebow and Link, {Brian K.} and Corrado Magnani and Marc Maynadie and James McKay and Mads Melbye and Lucia Miligi and Milne, {Roger L.} and Molina, {Thierry J.} and Alain Monnereau and Rebecca Montalvan and North, {Kari E.} and Novak, {Anne J.} and Kenan Onel and Purdue, {Mark P.} and Rand, {Kristin A.} and Elio Riboli and Jacques Riby and Eve Roman and Gilles Salles and Sborov, {Douglas W.} and Severson, {Richard K.} and Shanafelt, {Tait D.} and Smith, {Martyn T.} and Alexandra Smith and Song, {Kevin W.} and Lei Song and Southey, {Melissa C.} and Spinelli, {John J.} and Anthony Staines and Deborah Stephens and Sutherland, {Heather J.} and Kaitlyn Tkachuk and Thompson, {Carrie A.} and Herv{\'e} Tilly and Tinker, {Lesley F.} and Travis, {Ruth C.} and Jenny Turner and Vachon, {Celine M.} and Vajdic, {Claire M.} and {Van Den Berg}, Anke and {Van Den Berg}, {David J.} and Vermeulen, {Roel C.H.} and Paolo Vineis and Wang, {Sophia S.} and Elisabete Weiderpass and Weiner, {George J.} and Stephanie Weinstein and Doo, {Nicole Wong} and Yuanqing Ye and Meredith Yeager and Kai Yu and Anne Zeleniuch-Jacquotte and Yawei Zhang and Tongzhang Zheng and Elad Ziv and Joshua Sampson and Nilanjan Chatterjee and Kenneth Offit and Wendy Cozen and Xifeng Wu and Cerhan, {James R.} and Chanock, {Stephen J.} and Slager, {Susan L.} and Nathaniel Rothman",

note = "Funding Information: TS received research support to his institution from Genetech, Pharacyclics, AbbVie, Cephalon, Hospira, GlaxoSmithKline, Polyphenon E International, Merck, and Celgene and holds a patent (US14/292,075) on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia. KS received research funding from Janssen Pharmaceuticals AB for research unrelated to this project. CH received honoraria from Novartis, Amgen, Servier/Pfizer, and Gilead Sciences, acted as a consultant or advisor to Roche, Celgene, Janssen-Cilag, Gilead Sciences, Takeda, Miltenyi Biotec, Abbvie, and ADC Therapeutics, and received travel, accommodations and/or expenses from Roche, Celgene, and Amgen. KO is currently a full-time employee at Sema4. TH is on the data monitoring boards for Seagen and Tessa Therapeutics, scientific advisory boards for Eli Lilly, Morpohsys, Incyte, Biegene, and Loxo Oncology, and received research support from Genentech and Sorrento Therapeutics. The other authors declare no competing interests. Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The authors thank Mr. William Wheeler (Information Management Services, Inc.) for his analytic support. A complete list of funding sources and acknowledgements for individual studies is listed in the Supplementary Material. Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = dec,

doi = "10.1038/s41375-022-01711-0",

language = "English",

volume = "36",

pages = "2835–2844",

journal = "Leukemia",

issn = "0887-6924",

publisher = "Nature Publishing Group",

}

Berndt, SI, Vijai, J, Benavente, Y, Camp, NJ, Nieters, A, Wang, Z, Smedby, KE, Kleinstern, G, Hjalgrim, H, Besson, C, Skibola, CF, Morton, LM, Brooks-Wilson, AR, Teras, LR, Breeze, C, Arias, J, Adami, HO, Albanes, D, Anderson, KC, Ansell, SM, Bassig, B, Becker, N, Bhatti, P, Birmann, BM, Boffetta, P, Bracci, PM, Brennan, P, Brown, EE, Burdett, L, Cannon-Albright, LA, Chang, ET, Chiu, BCH, Chung, CC, Clavel, J, Cocco, P, Colditz, G, Conde, L, Conti, DV, Cox, DG, Curtin, K, Casabonne, D, De Vivo, I, Diver, WR, Dogan, A, Edlund, CK, Foretova, L, Fraumeni, JF, Gabbas, A, Ghesquières, H, Giles, GG, Glaser, S, Glenn, M, Glimelius, B, Gu, J, Habermann, TM, Haiman, CA, Haioun, C, Hofmann, JN, Holford, TR, Holly, EA, Hutchinson, A, Izhar, A, Jackson, RD, Jarrett, RF, Kaaks, R, Kane, E, Kolonel, LN, Kong, Y, Kraft, P, Kricker, A, Lake, A, Lan, Q, Lawrence, C, Li, D, Liebow, M, Link, BK, Magnani, C, Maynadie, M, McKay, J, Melbye, M, Miligi, L, Milne, RL, Molina, TJ, Monnereau, A, Montalvan, R, North, KE, Novak, AJ, Onel, K, Purdue, MP, Rand, KA, Riboli, E, Riby, J, Roman, E, Salles, G, Sborov, DW, Severson, RK, Shanafelt, TD, Smith, MT, Smith, A, Song, KW, Song, L, Southey, MC, Spinelli, JJ, Staines, A, Stephens, D, Sutherland, HJ, Tkachuk, K, Thompson, CA, Tilly, H, Tinker, LF, Travis, RC, Turner, J, Vachon, CM, Vajdic, CM, Van Den Berg, A, Van Den Berg, DJ, Vermeulen, RCH, Vineis, P, Wang, SS, Weiderpass, E, Weiner, GJ, Weinstein, S, Doo, NW, Ye, Y, Yeager, M, Yu, K, Zeleniuch-Jacquotte, A, Zhang, Y, Zheng, T, Ziv, E, Sampson, J, Chatterjee, N, Offit, K, Cozen, W, Wu, X, Cerhan, JR, Chanock, SJ, Slager, SL & Rothman, N 2022, 'Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes', Leukemia, vol. 36, pp. 2835–2844. https://doi.org/10.1038/s41375-022-01711-0

TY - JOUR

T1 - Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

AU - Berndt, Sonja I.

AU - Vijai, Joseph

AU - Benavente, Yolanda

AU - Camp, Nicola J.

AU - Nieters, Alexandra

AU - Wang, Zhaoming

AU - Smedby, Karin E.

AU - Kleinstern, Geffen

AU - Hjalgrim, Henrik

AU - Besson, Caroline

AU - Skibola, Christine F.

AU - Morton, Lindsay M.

AU - Brooks-Wilson, Angela R.

AU - Teras, Lauren R.

AU - Breeze, Charles

AU - Arias, Joshua

AU - Adami, Hans Olov

AU - Albanes, Demetrius

AU - Anderson, Kenneth C.

AU - Ansell, Stephen M.

AU - Bassig, Bryan

AU - Becker, Nikolaus

AU - Bhatti, Parveen

AU - Birmann, Brenda M.

AU - Boffetta, Paolo

AU - Bracci, Paige M.

AU - Brennan, Paul

AU - Brown, Elizabeth E.

AU - Burdett, Laurie

AU - Cannon-Albright, Lisa A.

AU - Chang, Ellen T.

AU - Chiu, Brian C.H.

AU - Chung, Charles C.

AU - Clavel, Jacqueline

AU - Cocco, Pierluigi

AU - Colditz, Graham

AU - Conde, Lucia

AU - Conti, David V.

AU - Cox, David G.

AU - Curtin, Karen

AU - Casabonne, Delphine

AU - De Vivo, Immaculata

AU - Diver, W. Ryan

AU - Dogan, Ahmet

AU - Edlund, Christopher K.

AU - Foretova, Lenka

AU - Fraumeni, Joseph F.

AU - Gabbas, Attilio

AU - Ghesquières, Hervé

AU - Giles, Graham G.

AU - Glaser, Sally

AU - Glenn, Martha

AU - Glimelius, Bengt

AU - Gu, Jian

AU - Habermann, Thomas M.

AU - Haiman, Christopher A.

AU - Haioun, Corinne

AU - Hofmann, Jonathan N.

AU - Holford, Theodore R.

AU - Holly, Elizabeth A.

AU - Hutchinson, Amy

AU - Izhar, Aalin

AU - Jackson, Rebecca D.

AU - Jarrett, Ruth F.

AU - Kaaks, Rudolph

AU - Kane, Eleanor

AU - Kolonel, Laurence N.

AU - Kong, Yinfei

AU - Kraft, Peter

AU - Kricker, Anne

AU - Lake, Annette

AU - Lan, Qing

AU - Lawrence, Charles

AU - Li, Dalin

AU - Liebow, Mark

AU - Link, Brian K.

AU - Magnani, Corrado

AU - Maynadie, Marc

AU - McKay, James

AU - Melbye, Mads

AU - Miligi, Lucia

AU - Milne, Roger L.

AU - Molina, Thierry J.

AU - Monnereau, Alain

AU - Montalvan, Rebecca

AU - North, Kari E.

AU - Novak, Anne J.

AU - Onel, Kenan

AU - Purdue, Mark P.

AU - Rand, Kristin A.

AU - Riboli, Elio

AU - Riby, Jacques

AU - Roman, Eve

AU - Salles, Gilles

AU - Sborov, Douglas W.

AU - Severson, Richard K.

AU - Shanafelt, Tait D.

AU - Smith, Martyn T.

AU - Smith, Alexandra

AU - Song, Kevin W.

AU - Song, Lei

AU - Southey, Melissa C.

AU - Spinelli, John J.

AU - Staines, Anthony

AU - Stephens, Deborah

AU - Sutherland, Heather J.

AU - Tkachuk, Kaitlyn

AU - Thompson, Carrie A.

AU - Tilly, Hervé

AU - Tinker, Lesley F.

AU - Travis, Ruth C.

AU - Turner, Jenny

AU - Vachon, Celine M.

AU - Vajdic, Claire M.

AU - Van Den Berg, Anke

AU - Van Den Berg, David J.

AU - Vermeulen, Roel C.H.

AU - Vineis, Paolo

AU - Wang, Sophia S.

AU - Weiderpass, Elisabete

AU - Weiner, George J.

AU - Weinstein, Stephanie

AU - Doo, Nicole Wong

AU - Ye, Yuanqing

AU - Yeager, Meredith

AU - Yu, Kai

AU - Zeleniuch-Jacquotte, Anne

AU - Zhang, Yawei

AU - Zheng, Tongzhang

AU - Ziv, Elad

AU - Sampson, Joshua

AU - Chatterjee, Nilanjan

AU - Offit, Kenneth

AU - Cozen, Wendy

AU - Wu, Xifeng

AU - Cerhan, James R.

AU - Chanock, Stephen J.

AU - Slager, Susan L.

AU - Rothman, Nathaniel

N1 - Funding Information: TS received research support to his institution from Genetech, Pharacyclics, AbbVie, Cephalon, Hospira, GlaxoSmithKline, Polyphenon E International, Merck, and Celgene and holds a patent (US14/292,075) on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia. KS received research funding from Janssen Pharmaceuticals AB for research unrelated to this project. CH received honoraria from Novartis, Amgen, Servier/Pfizer, and Gilead Sciences, acted as a consultant or advisor to Roche, Celgene, Janssen-Cilag, Gilead Sciences, Takeda, Miltenyi Biotec, Abbvie, and ADC Therapeutics, and received travel, accommodations and/or expenses from Roche, Celgene, and Amgen. KO is currently a full-time employee at Sema4. TH is on the data monitoring boards for Seagen and Tessa Therapeutics, scientific advisory boards for Eli Lilly, Morpohsys, Incyte, Biegene, and Loxo Oncology, and received research support from Genentech and Sorrento Therapeutics. The other authors declare no competing interests. Funding Information: This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication. The authors thank Mr. William Wheeler (Information Management Services, Inc.) for his analytic support. A complete list of funding sources and acknowledgements for individual studies is listed in the Supplementary Material. Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2022/12

Y1 - 2022/12

N2 - Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

AB - Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

UR - http://www.scopus.com/inward/record.url?scp=85140325134&partnerID=8YFLogxK

U2 - 10.1038/s41375-022-01711-0

DO - 10.1038/s41375-022-01711-0

M3 - Article

C2 - 36273105

AN - SCOPUS:85140325134

VL - 36

SP - 2835

EP - 2844

JO - Leukemia

JF - Leukemia

SN - 0887-6924

ER -

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

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