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.

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.

Objectives: Assess differences in movement behaviours within the 24-hour cycle, including light intensity physical activity (LPA), moderate-to-vigorous physical activity (MVPA), sedentary time and sleep, before and during the COVID-19 pandemic and assess these differences stratified by several relevant factors in a subcohort of the Cancer Prevention Study-3. Design and setting: US-based longitudinal cohort study (2018-August 2020). Participants: N=1992 participants, of which 1304 (65.5%) are women, and 1512 (75.9%) are non-Latino white, with a mean age 57.0 (9.8) years. Measures: Age, sex, race/ethnicity, education; self-reported LPA, MVPA, sedentary time and sleep duration collected before and during the pandemic; pandemic-related changes in work, childcare and living arrangement; COVID-19 health history. Results: Compared to 2018, participants spent an additional 104 min/day sedentary, 61 fewer min/day in LPA and 43 fewer min/day in MVPA during the pandemic. Time spent sleeping was similar at the two time points. Differences in movement behaviours were more pronounced among men, those with a higher level of education, and those who were more active before the pandemic. Conclusions: From 2018 to Summer 2020, during the COVID-19 pandemic, US adults have made significant shifts in daily time spent in LPA, MVPA and sedentary. There is an urgent need to promote more physical activity and less sedentary time during this public health crisis to avoid sustaining these patterns long-term.

Background Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular (FL) and marginal zone (MZL) lymphoma using Mendelian randomization (MR) analysis. Methods GWAS data from the InterLymph Consortium were available for 2661 DLBCLs, 2179 CLLs, 2142 FLs, 824 MZLs, and 6221 controls. SNPs associated (P<5×10−8) with high-density lipoprotein (HDL, N=164), low-density lipoprotein (LDL, N=137), total cholesterol (TC, N=161), and triglycerides (TG, N=123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8% and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance-weighted method, estimating odds ratios (OR) per standard deviation, and 95% confidence intervals (CI). Results HDL was positively associated with DLBCL (OR=1.14, CI:1.00–1.30) and MZL (OR=1.09, CI:1.01–1.18), while TG was inversely associated with MZL risk (OR=0.90, CI:0.83–0.99) all at nominal significance (P<0.05). A positive trend was observed for HDL with FL risk (OR=1.08, CI:0.99–1.19; P=0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.