PT - JOURNAL ARTICLE AU - Tarjinder Singh AU - Mitja I. Kurki AU - David Curtis AU - Shaun M. Purcell AU - Lucy Crooks AU - Jeremy McRae AU - Jaana Suvisaari AU - Himanshu Chheda AU - Douglas Blackwood AU - Gerome Breen AU - Olli Pietiläinen AU - Sebastian S. Gerety AU - Muhammad Ayub AU - Moira Blyth AU - Trevor Cole AU - David Collier AU - Eve L. Coomber AU - Nick Craddock AU - Mark J. Daly AU - John Danesh AU - Marta DiForti AU - Alison Foster AU - Nelson B. Freimer AU - Daniel Geschwind AU - Mandy Johnstone AU - Shelagh Joss AU - Georg Kirov AU - Jarmo Körkkö AU - Outi Kuismin AU - Peter Holmans AU - Christina M. Hultman AU - Conrad Iyegbe AU - Jouko Lönnqvist AU - Minna Männikkö AU - Steve A. McCarroll AU - Peter McGuffin AU - Andrew M. McIntosh AU - Andrew McQuillin AU - Jukka S. Moilanen AU - Carmel Moore AU - Robin M. Murray AU - Ruth Newbury-Ecob AU - Willem Ouwehand AU - Tiina Paunio AU - Elena Prigmore AU - Elliott Rees AU - David Roberts AU - Jennifer Sambrook AU - Pamela Sklar AU - David St. Clair AU - Juha Veijola AU - James T. R. Walters AU - Hywel Williams AU - Swedish Schizophrenia Study AU - INTERVAL Study AU - DDD Study AU - UK10K Consortium AU - Patrick F. Sullivan AU - Matthew E. Hurles AU - Michael C. O'Donovan AU - Aarno Palotie AU - Michael J. Owen AU - Jeffrey C. Barrett TI - Rare loss-of-function variants in <em>KMT2F</em> are associated with schizophrenia and developmental disorders AID - 10.1101/036384 DP - 2016 Jan 01 TA - bioRxiv PG - 036384 4099 - http://biorxiv.org/content/early/2016/01/12/036384.short 4100 - http://biorxiv.org/content/early/2016/01/12/036384.full AB - Schizophrenia is a common, debilitating psychiatric disorder with a substantial genetic component. By analysing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls, and 1,077 parent-proband trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in KMT2F and risk for schizophrenia. In this dataset, we observed three de novo LoF mutations, seven LoF variants in cases, and none in controls (P = 3.3x10−9). To search for LoF variants in KMT2F in individuals without a known neuropsychiatric diagnosis, we examined the exomes of 45,376 individuals in the ExAC database and found only two heterozygous LoF variants, showing that KMT2F is significantly depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying KMT2F LoF variants also had varying degrees of learning difficulties. We further identified four KMT2F LoF carriers among 4,281 children with diverse, severe, undiagnosed developmental disorders, and two additional carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations show that LoF variants in KMT2F cause a range of neurodevelopmental disorders, including schizophrenia. Combined with previous common variant evidence, we more generally implicate epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, as an important mechanism in the pathogenesis of schizophrenia.