Genetic Heritability of Common Non-Hodgkin Lymphoma Subtypes.

Non-Hodgkin lymphoma (NHL) is comprised of multiple subtypes with distinct morphologic and clinical features. Although these subtypes are hypothesized to be etiologically distinct and common variants for specific subtypes have been identified, no studies have comprehensively evaluated the contribution of common genetic variants to the heritability of individual subtypes. We, therefore, used genome-wide association data from a large, multicenter study of the four most common subtypes of NHL to estimate the contribution of common SNPs to the heritability of NHL. Participants were genotyped using the Illumina OmniExpress, and data were available from 2,179 cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 2,142 cases of follicular lymphoma (FL), 2,661 cases of diffuse large B-cell lymphoma (DLBCL), 825 cases of marginal zone lymphoma (MZL) and 6,221 controls of European ancestry.We utilized genomewide complex trait analysis (GCTA) to estimate the proportion of phenotypic variance explained on a liability scale and to estimate the shared heritability between subtypes, adjusting for age, sex, study, and principal components. The proportion of variance explained for the four NHL subtypes combined was estimated to be 11.9% (95% CI: 8-17%) with substantial heterogeneity among NHL subtypes: 35.5% (95% CI: 24-50%) for CLL/SLL, 20.8% (95% CI: 12-32%) for FL, 10.4% (95% CI: 4-18%) for DLBCL, and 8.3% (95% CI: 0-23%) for MZL. Small but non-significant differences were observed by sex for the individual subtypes. Although the precision in the estimates was limited, an examination of the shared heritability between subtypes showed modest genetic correlations ranging from 0.20-0.86. FL and DLBCL, for example, showed a genetic correlation of 0.57 (±0.28). Exclusion of the HLA region, did not substantially affect the estimates for the individual subtypes or the shared heritability observed between subtypes, suggesting that the HLA region captures only a small portion of the variance explained. Overall, this study indicates that although there is some shared heritability across NHL subtypes, the genetic architecture of individual NHL subtypes is distinct and consideration of NHL subtypes is essential for discovering new variants associated with susceptibility.