期刊
TRANSLATIONAL PSYCHIATRY
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41398-018-0354-9
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资金
- Brain & Behavior Research Foundation [NARSAD: 22597]
- Binational Science Foundation [2011378]
- National Institute of Mental Health of the National Institutes of Health [U01MH101722]
- Division Of Physics
- Direct For Mathematical & Physical Scien [2011378] Funding Source: National Science Foundation
The 22q11.2 deletion is a strong, but insufficient, first hit genetic risk factor for schizophrenia (SZ). We attempted to identify second hits from the entire genome in a unique multiplex 22q11.2 deletion syndrome (DS) family. Bioinformatic analysis of whole-exome sequencing and comparative-genomic hybridization array identified de novo and inherited, rare and damaging variants, including copy number variations, outside the 22q11.2 region. A specific 22q11.2-haplotype was associated with psychosis. The interaction of the identified second hits with the 22q11.2 haploinsufficiency may affect neurodevelopmental processes, including neuron projection, cytoskeleton activity, and histone modification in 22q11.2DS-ralated psychosis. A larger load of variants, involved in neurodevelopment, in combination with additional molecular events that affect sensory perception, olfactory transduction and G-protein-coupled receptor signaling may account for the development of 22q11.2DS-related SZ. Comprehensive analysis of multiplex families is a promising approach to the elucidation of the molecular pathophysiology of 22q11.2DS-related SZ with potential relevance to treatment.
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