• [Biological Psychiatry] Low-level brain somatic mutations are implicated in schizophrenia
  • 관리자 |
  • 2021-05-31 09:40:16|
  • 130
Title : Low-level brain somatic mutations are implicated in schizophrenia

Author : Myeong-Heui Kim, Il Bin Kim, Junehawk Lee, Do HyeonCha, Sang MinPark, Ja Hye Kim, Ryunhee Kim, Jun SungPark, Yohan An, Kyungdeok Kim, Seyeon Kim, Maree J.Webster, Sanghyeon Kim, Jeong Ho Lee



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.


We performed deep whole exome sequencing (average read depth > 550×) of matched dorsolateral prefrontal cortex and peripheral tissues from 27 patients with SCZ and 31 age-matched control individuals, followed by comprehensive and strict analysis of somatic mutations, including mutagenesis signature, substitution patterns, and involved pathways. In particular, we explored the impact of deleterious mutations in GRIN2B through primary neural culture.


We identified an average of 4.9 and 5.6 somatic mutations per exome per brain in patients with SCZ and control individuals, respectively. These mutations presented with average variant allele frequencies of 8.0% in patients with SCZ and 7.6% in control individuals. Although mutational profiles, such as the number and type of mutations, showed no significant difference between patients with SCZ and control individuals, somatic mutations in SCZ brains were significantly enriched for SCZ-related pathways, including dopamine receptor, glutamate receptor, and long-term potentiation pathways. Furthermore, we showed that brain somatic mutations in GRIN2B (encoding glutamate ionotropic NMDA receptor subunit 2B), which were found in two patients with SCZ, disrupted the location of GRIN2B across the surface of dendrites among primary cultured neurons.


Taken together, this study shows that brain somatic mutations are associated with the pathogenesis of SCZ.


Brain somatic mutations
Genetic architecture
Glutamate receptor signaling pathways
Grin2B, Low-level somatic mutations