Rare loss-of-function variants in KMT2F are associated with schizophrenia and developmental disorders
Mitja I. Kurki,
Shaun M. Purcell,
Sebastian S. Gerety,
Eve L. Coomber,
Mark J. Daly,
Nelson B. Freimer,
Christina M Hultman,
Steve A. McCarroll,
Andrew M McIntosh,
Jukka S. Moilanen,
Robin M Murray,
David St. Clair,
Swedish Schizophrenia Study,
Patrick F Sullivan,
Matthew E Hurles,
Michael C O'Donovan,
Michael J Owen,
Jeffrey C Barrett
Posted 12 Jan 2016
bioRxiv DOI: 10.1101/036384 (published DOI: 10.1038/nn.4267)
Posted 12 Jan 2016
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.
- Downloaded 1,023 times
- Download rankings, all-time:
- Site-wide: 20,317
- In genomics: 2,030
- Year to date:
- Site-wide: 91,998
- Since beginning of last month:
- Site-wide: 88,742
Downloads over time
Distribution of downloads per paper, site-wide
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!