Impact of insomnia on ovarian cancer risk and survival: a Mendelian randomization studyResearch in context
Heming Wang,
Brett M. Reid,
Rebecca C. Richmond,
Jacqueline M. Lane,
Richa Saxena,
Brian D. Gonzalez,
Brooke L. Fridley,
Susan Redline,
Shelley S. Tworoger,
Xuefeng Wang
Affiliations
Heming Wang
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
Brett M. Reid
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
Rebecca C. Richmond
Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; NIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, UK
Jacqueline M. Lane
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
Richa Saxena
Center for Genomic Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
Brian D. Gonzalez
Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, FL, USA
Brooke L. Fridley
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA; Children's Mercy Hospital, Kansas City, MO, USA
Susan Redline
Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
Shelley S. Tworoger
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA; Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
Xuefeng Wang
Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA; Corresponding author. Moffitt Cancer Center, Tampa, FL 33647, USA.
Summary: Background: Insomnia is the most common sleep disorder in patients with epithelial ovarian cancer (EOC). We investigated the causal association between genetically predicted insomnia and EOC risk and survival through a two-sample Mendelian randomization (MR) study. Methods: Insomnia was proxied using genetic variants identified in a genome-wide association study (GWAS) meta-analysis of UK Biobank and 23andMe. Using genetic associations with EOC risk and overall survival from the Ovarian Cancer Association Consortium (OCAC) GWAS in 66,450 women (over 11,000 cases with clinical follow-up), we performed Iterative Mendelian Randomization and Pleiotropy (IMRP) analysis followed by a set of sensitivity analyses. Genetic associations with survival and response to treatment in ovarian cancer study of The Cancer Genome Atlas (TCGA) were estimated controlling for chemotherapy and clinical factors. Findings: Insomnia was associated with higher risk of endometrioid EOC (OR = 1.60, 95% CI 1.05–2.45) and lower risk of high-grade serous EOC (HGSOC) and clear cell EOC (OR = 0.79 and 0.48, 95% CI 0.63–1.00 and 0.27–0.86, respectively). In survival analysis, insomnia was associated with shorter survival of invasive EOC (OR = 1.45, 95% CI 1.13–1.87) and HGSOC (OR = 1.4, 95% CI 1.04–1.89), which was attenuated after adjustment for body mass index and reproductive age. Insomnia was associated with reduced survival in TCGA HGSOC cases who received standard chemotherapy (OR = 2.48, 95% CI 1.13–5.42), but was attenuated after adjustment for clinical factors. Interpretation: This study supports the impact of insomnia on EOC risk and survival, suggesting treatments targeting insomnia could be pivotal for prevention and improving patient survival. Funding: National Institutes of Health, National Cancer Institute. Full funding details are provided in acknowledgments.
