Identification of somatic mutations in dorsolateral prefrontal cortex underlying schizophrenia

Abstract

Somatic mutations arising from the brain have recently emerged as significant contributors to neurodevelopmental disorders, including childhood intractable epilepsy and cortical malformations. However, whether brain somatic mutations are implicated in schizophrenia (SCZ) is not well established. Here, I performed deep whole exome sequencing (average read depth >550x) of matched dorsolateral prefrontal cortex and peripheral tissues from 27 SCZ and 31 age-matched control individuals, followed by comprehensive and strict analysis of somatic mutations such as mutagenesis signature, substitution patterns and involved pathways of somatic mutations. Particularly, I explored the impact of deleterious mutations in GRIN2B through primary neural culture. As results, I identified an average of 4.9 and 5.6 somatic mutations per exome per brain in SCZ and control individuals, respectively. These mutations presented with average variant allele frequencies of 8.0% in SCZ and 7.6% in controls. Although mutational profiles, such as the number and type of mutations, showed no significant difference between SCZ and controls, somatic mutations in SCZ brains were significantly enriched for SCZ-related pathways, including dopamine receptor, glutamate receptor, and synaptogenesis signaling pathways. Furthermore, I showed that brain-specific somatic mutations in GRIN2B (encoding glutamate ionotropic receptor NMDA type subunit 2B), which were recurrently found in two SCZ patients, disrupted the location of GRIN2B across the surface of dendrites among primary cultured neurons. Taken together, this study shows that the brain somatic mutations are associated with the pathogenesis of SCZ.