Date of Award

Fall 2023

Document Type

Open Access Dissertation


Epidemiology and Biostatistics

First Advisor

Alyssa Clay-Gilmour


Background: Circadian rhythm disruption and sleep have been widely studied for their roles in immunity and cancer development. Evidence for an association of circadian rhythm and sleep traits with multiple myeloma (MM) risk is inconclusive. No studies have investigated these traits in relation to monoclonal gammopathy of undetermined significance (MGUS). Given that MGUS precedes almost all MM cases, investigating sleep and circadian rhythm in relation to both MM and MGUS is necessary. The purpose of this dissertation was to explore the genetic influences of circadian rhythm and sleep traits on the risk of MGUS and MM. Methods: Data were leveraged from 744 MGUS cases, 879 MGUS controls, 2344 MM cases, and 2327 MM controls within InterLymph. Single nucleotide polymorphisms (SNPs) associated (p < 5 × 10-8) with circadian rhythm-sleep traits (morningness, excessive daytime sleepiness, insomnia, sleep duration, short sleep, and long sleep) were selected for inclusion into this study. We investigated the genetic susceptibility of the chronotype and sleep traits in the MGUS and MM populations by calculating heritability estimates and genetic correlations. We further examined the genetic associations between the circadian rhythm-sleep traits and MGUS and MM risk by performing two-sample Mendelian randomization and polygenic risk score (PRS) analysis. Results: The studied circadian rhythm-sleep traits explained less than 5% of the phenotypic variance in MGUS and less than 1% of the phenotypic variance in MM. In the primary MR analysis, there was no evidence that the genetically proxied circadian rhythm-sleep traits were associated with risk of MGUS or MM. In sensitivity analyses, genetically proxied short sleep was inversely associated with both MGUS and MM (ORMGUS: 0.37, 95% CI: 0.14, 0.94, ORMM: 0.59, 95% CI: 0.37, 0.96). The inverse associations between short sleep and MGUS and MM persisted in the PRS analysis. In addition, morningness and sleep duration PRSs were positively associated with MGUS, while excessive daytime sleepiness and sleep duration PRSs were positively associated with MM. There was heterogeneity in these associations within stratum of sex and age. Conclusions: In conclusion, we found that the circadian rhythm and sleep traits in MGUS and MM populations are not strongly heritable. Findings from the MR and PRS analysis provide support for an association between circadian rhythm, sleep traits, MGUS, and MM. Future studies in larger study populations are warranted to confirm these findings.


© 2024, Brittany Crawford

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