| 1 | Neuron 2014 May 82: 773-80 |
|---|---|
| PMID | 24853937 |
| Title | Loss-of-function variants in schizophrenia risk and SETD1A as a candidate susceptibility gene. |
| Abstract | Loss-of-function (LOF) (i.e., nonsense, splice site, and frameshift) variants that lead to disruption of gene function are likely to contribute to the etiology of neuropsychiatric disorders. Here, we perform a systematic investigation of the role of both de novo and inherited LOF variants in精神分裂症using exome sequencing data from 231 case and 34 control trios. We identify two de novo LOF variants in theSETD1Agene, which encodes a subunit of histone methyltransferase, a finding unlikely to have occurred by chance, and provide evidence for a more general role of chromatin regulators in精神分裂症risk. Transmission pattern analyses reveal that LOF variants are more likely to be transmitted to affected individuals than controls. This is especially true for private LOF variants in genes intolerant to functional genetic variation. These findings highlight the contribution of LOF mutations to the genetic architecture of精神分裂症and provide important insights into disease pathogenesis. |
| SCZ Keywords | 精神分裂症 |
| 2 | Neuron 2016 Mar 89: 940-7 |
| PMID | 26938441 |
| Title | 德11月o Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. |
| Abstract | We analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and精神分裂症(SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) 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 andSETD1Ashowing 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. |
| SCZ Keywords | 精神分裂症 |
| 3 | Nat. Neurosci. 2016 Apr 19: 571-7 |
| PMID | 26974950 |
| Title | Rare loss-of-function variants in SETD1A are associated with schizophrenia and developmental disorders. |
| Abstract | By analyzing the whole-exome sequences of 4,264精神分裂症cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants inSETD1Aand risk for精神分裂症(P = 3.3 � 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating thatSETD1Ais substantially depleted of LoF variants in the general population. Seven of the ten individuals with精神分裂症carryingSETD1ALoF variants also had learning difficulties. We further identified fourSETD1ALoF 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 inSETD1Acause a range of neurodevelopmental disorders, including精神分裂症. 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精神分裂症. |
| SCZ Keywords | 精神分裂症 |