@article {Singh036384, author = {Tarjinder Singh and Mitja I. Kurki and David Curtis and Shaun M. Purcell and Lucy Crooks and Jeremy McRae and Jaana Suvisaari and Himanshu Chheda and Douglas Blackwood and Gerome Breen and Olli Pietil{\"a}inen and Sebastian S. Gerety and Muhammad Ayub and Moira Blyth and Trevor Cole and David Collier and Eve L. Coomber and Nick Craddock and Mark J. Daly and John Danesh and Marta DiForti and Alison Foster and Nelson B. Freimer and Daniel Geschwind and Mandy Johnstone and Shelagh Joss and Georg Kirov and Jarmo K{\"o}rkk{\"o} and Outi Kuismin and Peter Holmans and Christina M. Hultman and Conrad Iyegbe and Jouko L{\"o}nnqvist and Minna M{\"a}nnikk{\"o} and Steve A. McCarroll and Peter McGuffin and Andrew M. McIntosh and Andrew McQuillin and Jukka S. Moilanen and Carmel Moore and Robin M. Murray and Ruth Newbury-Ecob and Willem Ouwehand and Tiina Paunio and Elena Prigmore and Elliott Rees and David Roberts and Jennifer Sambrook and Pamela Sklar and David St. Clair and Juha Veijola and James T. R. Walters and Hywel Williams and Swedish Schizophrenia Study and INTERVAL Study and DDD Study and UK10K Consortium and Patrick F. Sullivan and Matthew E. Hurles and Michael C. O{\textquoteright}Donovan and Aarno Palotie and Michael J. Owen and Jeffrey C. Barrett}, title = {Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders}, elocation-id = {036384}, year = {2016}, doi = {10.1101/036384}, publisher = {Cold Spring Harbor Laboratory}, abstract = {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.}, URL = {https://www.biorxiv.org/content/early/2016/01/12/036384}, eprint = {https://www.biorxiv.org/content/early/2016/01/12/036384.full.pdf}, journal = {bioRxiv} }