In the last decade, genetic analysis has aided lymphoma classification, alongside traditional phenotypic subdivision. Lymphomas exhibit sex differences in disease incidence and prevalence; therefore, scope existed to explore sex-specific genetic variation. Harnessing UK Biobank genetic data (185,000 females, 176,000 males), sex-specific genome-wide genetic variation significantly associated with lymphoma subtypes was determined in both autosomal and sex chromosome genes. Sex-specific genetic variation significantly associated with sex-related characteristics was also identified. Functional predictions for those genes containing significant (p<5x10-5) genetic variation was carried out via ViSEAGO. For each lymphoma subtype, approximately 10-12% of the genes containing significantly associated genetic variants were shared between the sexes, highlighting largely sex-specific profiles for lymphoma subtypes. Significantly associated X chromosome genetic variants were identified for Non-Hodgkin's lymphoma (NHL) and Diffuse large B-cell lymphoma (DLBCL), such as variants within SYTL5 (in males) and PPP2R3B (in females); genes previously implicated in haematological malignancy biological processes. Additionally, in female NHL patients, a genetic variant mapped to ESR1, the gene coding for oestrogen receptor-alpha was identified, adding to the body of evidence highlighting the relevance of oestrogen regulation for haematological malignancy subtypes. Indeed, up to 9.1% of overlap was observed between those genes containing significant genetic variation associated with specific lymphoma subtypes, and those significantly associated with oestrogen level determination. Gene ontology analysis further emphasised functional overlaps between lymphoma and oestrogen level determination in females, highlighting predicted involvement in epigenetic modification, gene expression, and signalling. This study revealed sex-specific genetic variation significantly associated with lymphoma, as well as hormone level determination, and revealed biological pathways potentially disrupted during lymphoma pathogenesis which are influenced by oestrogen. Exploring these pathways may advance our understanding of the sex-specificities of lymphoma, and may reveal therapeutic targets to advance patient care.

The authors have declared no competing interest.

This project is supported by funding from Health and Social Care Research and Development Division STL/5569/19 (https://research.hscni.net/) (AJM), UK Research and Innovation Medical Research Council MC_PC_20026 (https://www.ukri.org/councils/mrc/) (AJM), Science Foundation Ireland and the Department for the Economy, Northern Ireland partnership award 15/IA/3152 (https://www.economy-ni.gov.uk/investigators-programme-partnership-funded-projects) (AJM, PM). Sponsors or funders did not play any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data was derived from UK Biobank - 21727

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