Dataset Information

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

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.

Results

We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10^-6) 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 (β = 27.5, SE = 6.51, P = 2.4 × 10^-5). 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.

SUBMITTER: Moore A

PROVIDER: S-EPMC8494431 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

Moore Amy A Machiela Mitchell J MJ Machado Moara M Wang Sophia S SS Kane Eleanor E Slager Susan L SL Zhou Weiyin W Carrington Mary M Lan Qing Q Milne Roger L RL Birmann Brenda M BM Adami Hans-Olov HO Albanes Demetrius D Arslan Alan A AA Becker Nikolaus N Benavente Yolanda Y Bisanzi Simonetta S Boffetta Paolo P Bracci Paige M PM Brennan Paul P Brooks-Wilson Angela R AR Canzian Federico F Caporaso Neil N Clavel Jacqueline J Cocco Pierluigi P Conde Lucia L Cox David G DG Cozen Wendy W Curtin Karen K De Vivo Immaculata I de Sanjose Silvia S Foretova Lenka L Gapstur Susan M SM Ghesquières Hervè H Giles Graham G GG Glenn Martha M Glimelius Bengt B Gao Chi C Habermann Thomas M TM Hjalgrim Henrik H Jackson Rebecca D RD Liebow Mark M Link Brian K BK Maynadie Marc M McKay James J Melbye Mads M Miligi Lucia L Molina Thierry J TJ Monnereau Alain A Nieters Alexandra A North Kari E KE Offit Kenneth K Patel Alpa V AV Piro Sara S Ravichandran Vignesh V Riboli Elio E Salles Gilles G Severson Richard K RK Skibola Christine F CF Smedby Karin E KE Southey Melissa C MC Spinelli John J JJ Staines Anthony A Stewart Carolyn C Teras Lauren R LR Tinker Lesley F LF Travis Ruth C RC Vajdic Claire M CM Vermeulen Roel C H RCH Vijai Joseph J Weiderpass Elisabete E Weinstein Stephanie S Doo Nicole Wong NW Zhang Yawei Y Zheng Tongzhang T Chanock Stephen J SJ Rothman Nathaniel N Cerhan James R JR Dean Michael M Camp Nicola J NJ Yeager Meredith M Berndt Sonja I SI

Journal of translational genetics and genomics 20210617

<h4>Aim</h4>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.<h4>Methods</h4>We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B ...[more]

PMID: 34622145

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Dataset Information

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

Aim

Methods

Results

Conclusion

Publications

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

Similar Datasets

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