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To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP \u2013 induced osteoblast differentiation (p&lt;10\u221220). SMAD6 mutations nonetheless showed striking incomplete penetrance (&lt;60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases.<\/jats:p>","DOI":"10.7554\/elife.20125","type":"journal-article","created":{"date-parts":[[2016,9,8]],"date-time":"2016-09-08T09:01:24Z","timestamp":1473325284000},"source":"Crossref","is-referenced-by-count":188,"title":["Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8926-9692","authenticated-orcid":true,"given":"Andrew T","family":"Timberlake","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, United States"},{"name":"Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States"},{"name":"Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University 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