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Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders
- Source :
- Nature neuroscience, vol 19, iss 4
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.
- Subjects :
- Male
0301 basic medicine
Genome-wide association study
Bioinformatics
Cohort Studies
0302 clinical medicine
2.1 Biological and endogenous factors
Psychology
Aetiology
Finland
Exome sequencing
education.field_of_study
General Neuroscience
Serious Mental Illness
Mental Health
Autism spectrum disorder
Schizophrenia
Female
Cognitive Sciences
UK10 K Consortium
Biotechnology
INTERVAL Study
Population
Biology
Article
03 medical and health sciences
Clinical Research
Genetics
medicine
Humans
Genetic Predisposition to Disease
education
Swedish Schizophrenia Study
Genetic Association Studies
Loss function
DDD Study
Neurology & Neurosurgery
Methyltransferase complex
Human Genome
Neurosciences
Case-control study
Genetic Variation
Histone-Lysine N-Methyltransferase
medicine.disease
R1
Brain Disorders
030104 developmental biology
Neurodevelopmental Disorders
Case-Control Studies
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15461726 and 10976256
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Nature Neuroscience
- Accession number :
- edsair.doi.dedup.....d0c632121651699403386209467f890f