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Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders

By Tarjinder Singh, Mitja I. Kurki, David Curtis, Shaun M. Purcell, Lucy Crooks, Jeremy McRae, J. Suvisaari, Himanshu Chheda, Douglas Blackwood, Gerome Breen, Olli Pietiläinen, Sebastian S. Gerety, Muhammad Ayub, Moira Blyth, Trevor Cole, David Collier, Eve L. Coomber, Nick Craddock, Mark Daly, John Danesh, Marta DiForti, Alison Foster, Nelson B. Freimer, Daniel Geschwind, Mandy Johnstone, Shelagh Joss, Georg Kirov, Jarmo Körkkö, Outi Kuismin, Peter Holmans, Christina M Hultman, Conrad Iyegbe, Jouko Lönnqvist, Minna Männikkö, Steve A. McCarroll, Peter McGuffin, Andrew M McIntosh, Andrew McQuillin, Jukka S. Moilanen, Carmel Moore, Robin M Murray, Ruth Newbury-Ecob, Willem Ouwehand, T. Paunio, Elena Prigmore, Elliott Rees, David Roberts, Jennifer Sambrook, Pamela Sklar, David St. Clair, Juha Veijola, James T. R. Walters, Hywel Williams, Swedish Schizophrenia Study, INTERVAL Study, DDD Study, UK10K Consortium, Patrick F Sullivan, Matthew E Hurles, Michael C O'Donovan, Aarno Palotie, Michael J Owen, Jeffrey C Barrett

Posted 12 Jan 2016
bioRxiv DOI: 10.1101/036384 (published DOI: 10.1038/nn.4267)

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.

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