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.
Highlights
The goal of the present study was to investigate the association of homozygosity with the risk of four major non-Hodgkin lymphoma (NHL) subtypes: chronic lymphocytic leukemia/small chronic lymphocytic leukemia (CLL), diffuse large Bcell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL)
The other seven Genome-wide association studies (GWAS) were the University of California at San Francisco Molecular Epidemiology of Non-Hodgkin Lymphoma study (UCSF2)[23], the University of California at San Francisco Molecular Epidemiology of Non-Hodgkin Lymphoma study (UCSF1) combined with controls from the Nurses’ Health Study (NHS)[24], the Scandinavian Lymphoma Etiology Study (SCALE)[25], the Groupe d’Etude des Lymphomes de l’Adulte (GELA) study combined with controls from the European Prospective Investigation into Cancer, Chronic Diseases, Nutrition, and Lifestyles (EPIC), the Mayo Clinic Case-Control Study of Diffuse Large B-cell Lymphoma (Mayo), the Genetic Epidemiology of CLL Consortium (GEC), and the Utah Chronic Lymphocytic Leukemia Study (Utah)
We discovered a positive association between the risk of CLL and increased homozygosity as measured by FROH (β = 21.1, 95% standard error (SE) = 4.41, P = 1.6 × 10-6) and F3 (β = 27.5, SE = 6.51, P = 2.4 × 10-5) [Table 2] with limited evidence of between-study heterogeneity (Phet = 0.42 and 0.11, respectively) [Supplementary Table 3]
Summary
Disentangling the heritable component of non-Hodgkin lymphoma (NHL) and its subtypes is an active area of research. Studies have reported higher NHL subtype-specific risks for first-degree relatives of cases affected with a given NHL subtype[4,5], suggesting a degree of subtype specificity. These findings suggest genetic factors are important in NHL etiology and, in particular, the potential role of recessively acting genetic risk alleles, but they underscore the potential for genetic heterogeneity in susceptibility to different NHL subtypes. Genome-wide association studies (GWAS) have identified multiple susceptibility loci associated with four major subtypes of NHL[6,7,8,9,10,11], but a substantial fraction of the disease heritability remains unexplained. Recessively acting loci, those with low minor allele frequency, could be missed by current genome-wide scans and represent potential novel disease-associated loci
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