Identifying Molecular Features Associated with Psychoneurological Symptoms in Women with Breast Cancer Using Multivariate Mixed Models

Breast cancer (BC) is the second most common cancer among women. Research shows many women with BC experience anxiety, depression, and stress (ADS). Epigenetics has recently emerged as a potential mechanism for the development of depression.1 Although there are growing numbers of research studies indicating that epigenetic changes are associated with ADS, there is currently no evidence that this association is present in women with BC. The goal of this study was to identify high-throughput methylation sites (CpG sites) that are associated with three psychoneurological symptoms (ADS) in women with BC. Traditionally, univariate models have been used to examine the relationship between methylation sites and each psychoneurological symptom; nevertheless, ADS can be treated as a cluster of related symptoms and included together in a multivariate linear model. Hence, an overarching goal of this study is to compare and contrast univariate and multivariate models when identifying methylation sites associated with ADS in women with BC. When fitting separate linear regression models for each ADS scale, 3 among 285,173 CpG sites tested were significantly associated with depression. Two significant CpG sites are located on their respective genes FAM101A and FOXJ1, and the third site cannot be mapped to any known gene at this time. In contrast, the multivariate models identified 8,535 ADS-related CpG sites. In conclusion, when analyzing correlated psychoneurological symptom outcomes, multivariate models are more powerful and thus are recommended.