RT Journal Article SR Electronic T1 Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders JF bioRxiv FD Cold Spring Harbor Laboratory SP 036384 DO 10.1101/036384 A1 Tarjinder Singh A1 Mitja I. Kurki A1 David Curtis A1 Shaun M. Purcell A1 Lucy Crooks A1 Jeremy McRae A1 Jaana Suvisaari A1 Himanshu Chheda A1 Douglas Blackwood A1 Gerome Breen A1 Olli Pietiläinen A1 Sebastian S. Gerety A1 Muhammad Ayub A1 Moira Blyth A1 Trevor Cole A1 David Collier A1 Eve L. Coomber A1 Nick Craddock A1 Mark J. Daly A1 John Danesh A1 Marta DiForti A1 Alison Foster A1 Nelson B. Freimer A1 Daniel Geschwind A1 Mandy Johnstone A1 Shelagh Joss A1 Georg Kirov A1 Jarmo Körkkö A1 Outi Kuismin A1 Peter Holmans A1 Christina M. Hultman A1 Conrad Iyegbe A1 Jouko Lönnqvist A1 Minna Männikkö A1 Steve A. McCarroll A1 Peter McGuffin A1 Andrew M. McIntosh A1 Andrew McQuillin A1 Jukka S. Moilanen A1 Carmel Moore A1 Robin M. Murray A1 Ruth Newbury-Ecob A1 Willem Ouwehand A1 Tiina Paunio A1 Elena Prigmore A1 Elliott Rees A1 David Roberts A1 Jennifer Sambrook A1 Pamela Sklar A1 David St. Clair A1 Juha Veijola A1 James T. R. Walters A1 Hywel Williams A1 Swedish Schizophrenia Study A1 INTERVAL Study A1 DDD Study A1 UK10K Consortium A1 Patrick F. Sullivan A1 Matthew E. Hurles A1 Michael C. O'Donovan A1 Aarno Palotie A1 Michael J. Owen A1 Jeffrey C. Barrett YR 2016 UL http://biorxiv.org/content/early/2016/01/12/036384.abstract 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.