Quantitative trait loci analysis of prepulse inhibition using exome data from inbred mouse strains and its application to the identification of schizophrenia susceptibility genes

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461759
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: TOYOTA TOMOKO 国立研究開発法人理化学研究所, 脳科学総合研究センター, 客員研究員 (20392045)
• Co-Investigator(Renkei-kenkyūsha): shimogori Tomomi 国立研究開発法人理化学研究所, 脳科学総合研究センター, チームリーダー (30391981)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 統合失調症 / 中間表現型 / 感覚情報フィルター / マウス近交系 / 量的遺伝子座解析 / CDH23遺伝子 / ゲノム編集 / エキソーム解析

Outline of Final Research Achievements

Fine mapping of pre-pulse inhibition - quantitative trait loci (PPI-QTL) by using exonic variants in C57BL/6N and C3H/HeN mouse strains has revealed the Cdh23 (Cadherin-Related 23) as a putative candidate gene and a splice site mutation is suggested to be causal for PPI modulation. We have validated the role of Cdh23 in C3H/He mouse strain with poor PPI, by ‘knocking in’ the non-causal variant to rescue the lowered PPI by using CRISPR/Cas9 system. We further clarified the expression pattern of Cdh23 in mice and the neurodevelopment-dependent expression profie of CDH23 in human iPS-derived cells. We have also identified multiple rare variants in schizophrenia samples. These results should provide novel insight into the complex genetic network pertaining to sensorimotor gating function and underlying neural mechanism of schizophrenia.

Free Research Field

精神医学、精神科遺伝学