Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network

Abstract

SUMMARY Genes disrupted in schizophrenia may be revealed by de novo mutations in affected persons from otherwise healthy families. Furthermore, during normal brain development, genes are expressed in patterns specific to developmental stage and neuroanatomical structure. We identified de novo mutations in persons with schizophrenia, then mapped the responsible genes onto transcriptome profiles of normal human brain tissues from age 13 weeks gestation to adulthood. In the dorsolateral and ventrolateral prefrontal cortex during fetal development, genes harboring damaging de novo mutations in schizophrenia formed a network significantly enriched for transcriptional co-expression and protein interaction. The 50 genes in the network function in neuronal migration, synaptic transmission, signaling, transcriptional regulation, and transport. These results suggest that disruptions of fetal prefrontal cortical neurogenesis are critical to the pathophysiology of schizophrenia. These results also support the feasibility of integrating genomic and transcriptome analyses to map critical neurodevelopmental processes in time and space in the brain.

The genomics of schizophrenia: update and implications

“…Evaluation of 166 schizophrenia cases in a search for variants associated with treatment resistance or notably strong family history failed to identify any exonic variants (28). Gulsuner et al conducted exome sequencing in family constellations selected to maximize the chances of observing de novo mutations; no genes were identified, although there was a slight excess of de novo mutations predicted to damage proteins (61).…”

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

“…Several groups have attempted to leverage this convergence by seeking stages of brain development and anatomical regions of the brain at which known genetic risk factors are expressed. Such convergence has been observed in the pre-frontal cortex during mid-fetal development in both ASD [72][73][74] and schizophrenia [75]. These approaches show the potential for rigorously identified genetic risk factors to be leveraged to reveal fundamental insights into the pathology of neuropsychiatric disorders.…”

Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity

“…11,12 Reads were aligned to the human reference genome (hg19) using the Burrows-Wheeler aligner. 13 Single nucleotide and small insertion-deletion (indel) variants were called by three independent bioinformatics pipelines, as previously described 12,14,15 and results jointly analyzed. Alignment to the whole genome facilitated exclusion of variants that fell in pseudogenes.…”