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Concord Clinical School, University of Sydney, Concord, New South Wales 2139, Australia.
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Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA.
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Department of Epidemiology, Brown University, Providence, RI 02903, USA.
Correspondence to: Sonja I. Berndt, Division of Cancer Epidemiology & Genetics, National Cancer Institute, NIH, 9609
Medical Center Drive, Room 6E610, MSC 9771, Rockville, MD 20850, USA. E-mail: berndts@mail.nih.gov
How to cite this article: Moore A, Machiela MJ, Machado M, Wang SS, Kane E, Slager SL, Zhou W, Carrington M, Lan Q, Milne
RL, Birmann BM, Adami HO, Albanes D, Arslan AA, Becker N, Benavente Y, Bisanzi S, Boffetta P, Bracci PM, Brennan P, Brooks-
Wilson AR, Canzian F, Caporaso N, Clavel J, Cocco P, Conde L, Cox DG, Cozen W, Curtin K, Vivo ID, Sanjose Sd, Foretova L,
Gapstur SM, Ghesquières H, Giles GG, Glenn M, Glimelius B, Gao C, Habermann TM, Hjalgrim H, Jackson RD, Liebow M, Link
BK, Maynadie M, McKay J, Melbye M, Miligi L, Molina TJ, Monnereau A, Nieters A, North KE, Offit K, Patel AV, Piro S,
Ravichandran V, Riboli E, Salles G, Severson RK, Skibola CF, Smedby KE, Southey MC, Spinelli JJ, Staines A, Stewart C, Teras LR,
Tinker LF, Travis RC, Vajdic CM, Vermeulen RCH, Vijai J, Weiderpass E, Weinstein S, Doo NW, Zhang Y, Zheng T, Chanock SJ,
Rothman N, Cerhan JR, Dean M, Camp NJ, Yeager M, Berndt SI. Genome-wide homozygosity and risk of four non-Hodgkin
lymphoma subtypes. J Transl Genet Genom 2021;5:200-217. https://dx.doi.org/10.20517/jtgg.2021.08
Received: 1 Mar 2021 First Decision: 31 Mar 2021 Revised: 13 May 2021 Accepted: 28 May 2021 First online: 17 Jun 2021

Academic Editor: Sanjay Gupta Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of
homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate
both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity
and NHL risk.

Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic
lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808
marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation
on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an
inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific
autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic
regression and combined estimates across studies using random-effects meta-analysis.

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Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 ) and FL (β =
11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL
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(β = 27.5, SE = 6.51, P = 2.4 × 10 ). We did not find evidence of associations with specific ROH, suggesting that the
associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.

Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional
research is needed to identify the specific loci associated with NHL risk.

Keywords: Non-Hodgkin lymphoma, homozygosity, chronic lymphocytic leukemia, follicular lymphoma, diffuse
large B-cell lymphoma, marginal zone lymphoma

INTRODUCTION