Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare,
chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide
association study of WM/LPL in 530 unrelated cases and 4362 controls of European
ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171,
near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13
(rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles
are observed at a low frequency among controls (~2–3%) and occur in excess in affected
cases within families. In silico data suggest that rs116446171 may have functional importance,
and in functional studies, we demonstrate increased reporter transcription and proliferation in
cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully
elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk
and provide insights into genetic susceptibility to this malignancy
