Investigation into psychiatric disorder-associated loci that influence transcriptional noises in dopaminergic neurons induced from human iPS cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15785
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Osaka University
• Principal Investigator: HIROSE Naoki 大阪大学, 大学院医学系研究科, 特任助教(常勤) (90830167)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 遺伝子発現ノイズ / 量的形質遺伝子座 / tnQTL / ドパミン作動性ニューロン / シングルセル解析 / 遺伝的リスク / 精神疾患 / 統合失調症

Outline of Final Research Achievements

Although variation in gene expression among cells (“transcriptional noise”) has biological significance, how it is affected by genetic variants and what roles it plays in disorders remain elusive. This study aimed to explore association between transcriptional noise and the genetic risk of human psychiatric disorders. Analysis of genotype and single-cell RNA-seq data of iPS cells (donor N = ~215) determined more than 40,000 transcriptional noise quantitative trait loci (tnQTLs), which were enriched in cis-regulatory region of gene expression. Some tnQTLs are deemed as causative to the genetic risk of psychiatric disorders, suggesting that changes of transcriptional noise play roles in their pathophysiology.

Free Research Field

トランスクリプトーム

Academic Significance and Societal Importance of the Research Achievements

これまでのゲノムワイド関連解析によって、疾患の遺伝的リスクに関わるゲノムの多型が数多く見出されてきた。しかし、遺伝的リスクにつながる多型の大半は、遺伝子発現の量的形質遺伝子座（eQTL）ではないため、機能的に解釈できる多型は多くない。本研究の成果に基づき、発現ノイズの変化という新しい観点から多型と遺伝的リスクの関わりを機能的に解釈し、様々な疾患の分子病態を深く理解していけると考えられる。また、本研究にて同定したtnQTLは、発現ノイズの制御機構の理解にも役立てられる。