Joo, JihoonDowty, JamesMilne, RogerMing Wong, E.Dugue, Pierre-AntoineSexton, AdrienneChristian, AliceTrainer, AlisonShelling, AndrewBlackburn, AnnekeFazio, Anna DeEnglish, Dallas R.Lindeman, Geoffrey J.Campbell, Ian G.Hickie, Ian B.Tucker, Katherine M.Jenkins, Mark A.2019-12-112019-12-112041-1723http://hdl.handle.net/1885/192966Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case–control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.The Australian site of Breast Cancer Family Registry was supported by grant UM1 CA164920 from the USA National Cancer Institute. kConFab is supported by a grant from the National Breast Cancer Foundation. The MCCS methylation work was supported by the National Health and Medical Research Council (Grant number 1011618); and the Victorian Breast Cancer Research Consortium. M.C.S. is a Senior Research Fellow and J.L.H. is a Senior Principal Research Fellow of the National Health and Medical Research Council of Australia. This work was supported by an Early Career Research Award to JEJ from The University of Melbourne.application/pdfen-AU© The Author(s) 2018http://creativecommons.org/licenses/by/4.0/2018-02-2810.1038/s41467-018-03058-62019-07-28Creative Commons Attribution 4.0 International License