한빛사논문
- 조회894
KAIST
Myeong-Heui Kim1,8, Il Bin Kim1,2,8, Junehawk Lee3, Do Hyeon Cha1, Sang Min Park1, Ja Hye Kim1, Ryunhee Kim1, Jun Sung Park1,4, Yohan An1, Kyungdeok Kim5, Seyeon Kim1, Maree J. Webster6, Sanghyeon Kim6,* Jeong Ho Lee1,7,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
2Department of Psychiatry, Hanyang University Guri Hospital, Guri, Republic of Korea
3Center for Computational Science Platform, National Institute of Supercomputing and Networking, Korea Institute of Science and Technology Information, Daejeon 34141, Republic of Korea
4The European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridgeshire, CB10 1SD, United Kingdom
5Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon
6Stanley Medical Research Institute, Laboratory of Brain Research, 9800 Medical Center Drive, Suite C-050, Rockville MD 20850, United States
7SoVarGen, Inc., Daejeon 34141, Republic of Korea
8These authors contributed equally.
*Corresponding author
Abstract
Background
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.
Methods
We 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, including mutagenesis signature, substitution patterns, and involved pathways. Particularly, we explored the impact of deleterious mutations in GRIN2B through primary neural culture..
Results
We 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 long-term potentiation pathways. Furthermore, we showed that brain somatic mutations in GRIN2B (encoding glutamate ionotropic receptor NMDA type subunit 2B), which were found in two SCZ patients, disrupted the location of GRIN2B across the surface of dendrites among primary cultured neurons.
Conclusions
Taken together, this study shows that brain somatic mutations are associated with the pathogenesis of SCZ.
논문정보
- Research article
- 2021년 02월 (BRIC 등록일 2021-02-15)
- 국내(교신)+국외 연구진
- 의약학 > 신경의학
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