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We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis\/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP\u2009&lt;\u20090.8) included 10 linked SNPs in <jats:italic>tryptophan hydroxylase 2<\/jats:italic> (<jats:italic>TPH2<\/jats:italic>) (e.g. rs1386492: OR\u2009=\u20091.07, 95% CI 1.02\u20131.12), and a SNP in the <jats:italic>mitogen-activated protein kinase 8<\/jats:italic> (<jats:italic>MAPK8<\/jats:italic>) (rs10857561: OR\u2009=\u20091.11, 95% CI 1.04\u20131.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with <jats:italic>TPH2-<\/jats:italic> and MAPK-related SNPs (e.g. rs1386483<jats:sub><jats:italic>R<\/jats:italic><\/jats:sub> \u2227 rs1473473<jats:sub><jats:italic>D<\/jats:italic><\/jats:sub> \u2227 rs3729931<jats:sub><jats:italic>D<\/jats:italic><\/jats:sub>: OR\u2009=\u20091.20, 95% CI 1.09\u20131.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in <jats:italic>TPH2<\/jats:italic> and MAPK-genes that may impact the intricate network of circadian regulation.<\/jats:p>","DOI":"10.1007\/s10654-023-01048-7","type":"journal-article","created":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T17:01:31Z","timestamp":1696352491000},"page":"1053-1068","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Polymorphisms in genes of melatonin biosynthesis and signaling support the light-at-night hypothesis for breast 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