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Moore et al. J Transl Genet Genom 2021;5:200-217 https://dx.doi.org/10.20517/jtgg.2021.08 Page 9

Figure 1. Manhattan plots of log (P) values for the association between runs of homozygosity (ROH) and the risk of chronic
10
lymphocytic leukemia (CLL) (A) and follicular lymphoma (FL) (B). Here, ROH were divided into 500-kb bins across each chromosome,
and each bin was tested for its association with CLL or FL. No bins reached statistical significance after correction for multiple testing.

[6,9]
risk loci , leaving a sizable fraction that remains undiscovered. We discovered strong associations between
CLL and genome-wide homozygosity as measured by FROH and F3. These findings suggest that recessive
genetic variants are likely to contribute to risk.

[35]
CLL is a hematologic malignancy characterized by large-scale chromosomal alterations and is often
preceded by a long-lasting pre-malignant stage of monoclonal B-cell lymphocytosis (MBL) . It is possible
[36]
that cases with diagnosed CLL at the time of enrollment or those with unidentified MBL had tumor DNA in
their blood samples, and that some mosaic events may have been erroneously picked up as ROH or
homozygous genotypes due to the calling method utilized. This could have inflated our association results,
but our sensitivity analyses suggested that any influence of mosaicism on our findings was likely to be small.
We excluded CLL cases with DNA collected after diagnosis in the NCI NHL GWAS and saw similar results
to our primary analysis, suggesting that tumor contamination is unlikely to be responsible for the observed
association. Further sensitivity analysis excluding individuals with known 13q14 deletion in NCI NHL
GWAS showed that the associations between FROH and F3 and CLL were only slightly attenuated. We also