Rare loss-of-function variants in<i>KMT2F</i>are associated with schizophrenia and developmental disorders

Singh, Tarjinder; Kurki, Mitja; Curtis, David; Purcell, Shaun; Crooks, Lucy; McRae, Jeremy F.; Suvisaari, Jaana; Chheda, Himanshu; Blackwood, Douglas; Breen, Gerome; Pietiläinen, Olli; Gerety, Sebastian S.; Ayub, Muhammad; Blyth, Moira; Cole, Trevor; Collier, David A.; Coomber, Eve L.; Craddock, Nick; Daly, Mark J.; Danesh, John; Forti, Marta Di; Foster, Alison; Geschwind, Daniel H.; Johnstone, Mandy; Joss, Shelagh; Kirov, George; Körkkö, Jarmo; Kuismin, Outi; Holmans, Peter; Hultman, Christina M.; Iyegbe, Conrad; Lönnqvist, Jouko; Männikkö, Minna; McCarroll, Steven A.; McGuffin, Peter; McIntosh, Andrew M.; McQuillin, Andrew; Moilanen, Jukka S.; Moore, Carmel; Murray, Robin M.; Newbury‐Ecob, Ruth; Ouwehand, Willem H.; Paunio, Tiina; Prigmore, Elena; Rees, Elliott; Roberts, David; Sambrook, Jennifer; Sklar, Pamela; Clair, David St; Veijola, Juha; Walters, James; Williams, Hywel; Study, Swedish Schizophrenia; Study, Interval; Study, Ddd; Sullivan, Patrick F.; Hurles, Matthew E.; O’Donovan, Michael; Palotie, Aarno; Barrett, Jeffrey C.

doi:10.1101/036384

Cited by 7 publications

(8 citation statements)

References 54 publications

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“…Identification of an additional potentially functional de novo synonymous mutation in this gene and the accumulating evidence for involvement of the chromatin regulation pathway in neuropsychiatric diseases, including ASD and SCZ, further supports that SETD1A is a genuine susceptibility gene for SCZ. Notably, strong association of LOF mutations in SETD1A (also known as KMT2F ) with SCZ was confirmed by a recent large-scale study examining several tens of thousands of WES data (Singh et al, 2016). …”

Section: Discussionmentioning

confidence: 79%

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia

Takata

Ionita‐Laza

Gogos

et al. 2016

Neuron

130

101

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SUMMARY We analyze de novo synonymous mutations identified in autism spectrum disorders (ASD) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole exome sequencing (WES) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex-derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include “functional” synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk.

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Section: Discussionmentioning

confidence: 79%

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia

Takata

Ionita‐Laza

Gogos

et al. 2016

Neuron

130

101

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“…A risk score from exome variants could be combined with a polygenic risk score from common SNPs. It could also be combined with risk scores derived from identified rare variants which have been shown to have a major effect on risk, such as specific copy number variants and gene mutations (Raychaudhuri et al, 2010;Singh et al, 2016). A recent study of autism has demonstrated that in subjects who possess rare variants having major effects on risk for autism, common variants can increase this risk further (Weiner et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Construction of an Exome‐Wide Risk Score for Schizophrenia Based on a Weighted Burden Test

Curtis

2017

Annals of Human Genetics

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Polygenic risk scores obtained as a weighted sum of associated variants can be used to explore association in additional data sets and to assign risk scores to individuals. The methods used to derive polygenic risk scores from common SNPs are not suitable for variants detected in whole exome sequencing studies. Rare variants, which may have major effects, are seen too infrequently to judge whether they are associated and may not be shared between training and test subjects. A method is proposed whereby variants are weighted according to their frequency, their annotations and the genes they affect. A weighted sum across all variants provides an individual risk score. Scores constructed in this way are used in a weighted burden test and are shown to be significantly different between schizophrenia cases and controls using a five-way cross-validation procedure. This approach represents a first attempt to summarise exome sequence variation into a summary risk score, which could be combined with risk scores from common variants and from environmental factors. It is hoped that the method could be developed further.

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“…81 Most recently, a combined analysis of 4264 cases, 9343 controls, and 1077 trios (which included the exomes sequenced in the two 2014 papers) reported a significant excess of very rare (including de novo) gene-disrupting variants in the SETD1A (SET domain containing 1A) gene in schizophrenia patients, finding 10 in 5341 unrelated cases (0.19%) and none in 9343 controls. 3 This represents the first time that NGS has shown a statistically significant association between schizophrenia and a single candidate gene. SETD1A is involved in histone methylation and the association with schizophrenia further substantiates the report that common risk variants for psychiatric disorders may ag-gregate on histone methylation pathways.…”

Section: Schizophreniamentioning

confidence: 91%

“…gene in amyotrophic lateral sclerosis (ALS). 2 Strikingly, such analyses allow a direct investigation of the underlying architecture of disease, and the cases of ALS, schizophrenia, 3 and unpublished studies of epilepsy and other conditions show that it is the very rarest variants that carry the strongest signal of risk. These results illustrate two critical features about complex human diseases.…”

Section: S T a T E O F T H E A R Tmentioning

confidence: 99%

Neuropsychiatric genomics in precision medicine: diagnostics, gene discovery, and translation

Need

Goldstein

2016

Dialogues in Clinical Neuroscience

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Only a few years after its development, next-generation sequencing is rapidly becoming an essential part of clinical care for patients with serious neurological conditions, especially in the diagnosis of early-onset and severe presentations. Beyond this diagnostic role, there has been an explosion in definitive gene discovery in a range of neuropsychiatric diseases. This is providing new pointers to underlying disease biology and is beginning to outline a new framework for genetic stratification of neuropsychiatric disease, with clear relevance to both individual treatment optimization and clinical trial design. Here, we outline these developments and chart the expected impact on the treatment of neurological, neurodevelopmental, and psychiatric disease.

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Rare loss-of-function variants inKMT2Fare associated with schizophrenia and developmental disorders

Abstract: Rare% loss)of)function% variants% in% KMT2F% are% associated% with%schizophrenia%and%developmental%disorders%

Cited by 7 publications

References 54 publications

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia

Construction of an Exome‐Wide Risk Score for Schizophrenia Based on a Weighted Burden Test

Neuropsychiatric genomics in precision medicine: diagnostics, gene discovery, and translation

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