10 つの遺伝子の希少なコード変異は,統合失調症の重大なリスクを伴います
Tarjinder Singh1,2,3, Timothy Poterba4,5, David Curtis6,7
1Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. tsingh@broadinstitute.org.
Nature
|April 9, 2022
まとめ
10の遺伝子の超希少なコード変異は 統合失調症のリスクを大幅に高めます これらの遺伝子は脳の神経細胞で高度に発現し,シナプス機能に不可欠であり,統合失調症の病原性におけるグルタマタージックシステムの機能不全を意味する.
科学分野:
- 神経遺伝学
- 精神疾患
背景:
- 遺伝子の機能や病気を理解する鍵となるものです
- 統合失調症の病原体は 複雑な遺伝因子を伴います
研究 の 目的:
- 統合失調症の重大なリスクを伴う極まれなコード化変異 (URV) を特定する.
- 統合失調症のリスク遺伝子に関連する 生物学的な機能と経路を探求する
主な方法:
- 24,248人の統合失調症患者と97,322人の対照群の全エクソームシーケンシングデータのメタ分析.
- 統合失調症リスクに関連するURVを持つ遺伝子を特定するための統計分析 (P < 2. 14 × 10−6).
主要な成果:
- 重要な統合失調症リスクを与えるURVを持つ10の遺伝子 (ORs 3-50) と誤った発見率<5%で32の追加の遺伝子を特定した.
- 関連遺伝子は中枢神経系の神経細胞で高い発現を示し,シナプス形成,構造,機能に関与する.
- 自閉症スペクトル障害,,重度の神経発達障害と重なり合っている.
- 遺伝的危険因子の収束を示唆する,以前は一般的な変異分析から優先された遺伝子の希少変異リスクの濃縮が実証された.
結論:
- 特定の遺伝子の超希少なコード変異は 統合失調症の重要な危険因子です
- GRIN2AとGRIA3との関連によって支持されるグルタマタージックシステムの機能障害は,重要なメカニズム的仮説である.
- 統合失調症は他の神経発達および神経学的障害と遺伝的危険因子を共有していますが,異なる変異型が関与している可能性があります.
- 共通する遺伝的変異は統合失調症の危険に寄与し 共通の生物学的経路に収束する可能性があります
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