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

Berndt, Sonja I; Vijai, Joseph; Benavente, Yolanda; Camp, Nicola J; Nieters, Alexandra; Wang, Zhaoming; Smedby, Karin E; ... Rothman, Nathaniel; + view all (2022) Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes. Leukemia , 36 (12) pp. 2835-2844. 10.1038/s41375-022-01711-0. Green open access

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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.

Type: Article
Title: Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41375-022-01711-0
Publisher version: https://doi.org/10.1038/s41375-022-01711-0
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Cancer epidemiology, Cancer genetics, Risk factors
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10172326
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