Schizophrenia is a serious and complex mental illness whose pathogenesis is not yet clear. A recent study 1, scanning novo mutations (de novo mutation) in a group of schizophrenic patients, and the results with other mental disorders, such as autism, mental retardation and other mutations were compared, found These diseases have a similar genetic background and may cause disease by affecting the apparent regulation of the brain.
The sample from this study was from a family of 57 patients with disease, 15 of whom had a history of familial schizophrenia and the other with post-schoming schizophrenia. A total of 171 whole exomes were completed using NimbleGenSeqCap EZ Exome v2.0 to capture human exome sequences for parents and children in these families. On average, each sample obtained 94.2 M sequences, the exon group had an average depth of 67x, and 90% of the sequences had more than 10x coverage. SNPs found in sequences with a sequencing depth >10x were selected for new mutations in the patient's genome, including 59 new mutations and 6 by comparison with mutations in their parental samples, Exome Variant Server 6500 and 1000 Genomes. Indel has been verified by sanger sequencing.
Comparison of exomes in healthy people found that the frequency of heterosexual mutations was not significantly increased in patients with posterior schizophrenia, and the frequency of nonsense mutations increased by 3.5 times, and these nonsense mutations would have A greater likelihood of a single dose deficiency. In addition, from the gene function analysis, the genes in which these nonsense mutations are located have low tolerance to mutations (high RVIS values).
Table: List of the top 15% RVIS (Residual variation intolerance score) genes. From SE McCarthy et al. De novo mutations in schizophrenia implicate chromatinremodeling and support a genetic overlap with autism and intellectual disability. Mol Psychiatry. Molecular Psychiatry (2014), 1–7
Among the genes with new mutations, some are known to be associated with autism, such as AUTS2, CHD8, and MECP2 ; others are associated with mental retardation, such as HUWE1 and TRAPPC9 , indicating that the three diseases are intertwined in the genetic background of the disease. Functionally, CHD8, MECP2 and HUWE1 play a role in the epigenetic pathway of transcription , suggesting that epigenetic changes may play a role in the development of the disease.
The results of this study are similar to those of other neurodevelopmental abnormalities in sequencing, ie, mutations in mental disease-related genes may affect epigenetic regulation during brain development and cognitive formation , which may be The center of the pathogenesis mechanism may also be the target of treatment for such diseases.
1. SE McCarthy, J Gillis, M Kramer, J Lihm, S Yoon, Y Berstein, M Mistry, P Pavlidis, R Solomon, E Ghiban, E Antoniou, E Kelleher, C O'Brien, G Donohoe, M Gill, DW Morris, WR McCombie and A Corvin. De novo mutations in schizophrenia implicate chromatinremodeling and support a genetic overlap with autism andintegrative disability. Mol Psychiatry. advance online publication 29 April 2014; doi: 10.1038/mp.2014.29
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