全ゲノムシーケンシングは,骨密度と骨折の決定因子としてEN1を識別します
Hou-Feng Zheng1,2, Vincenzo Forgetta1,2, Yi-Hsiang Hsu3,4,5
1Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.
Nature
|September 15, 2015
まとめ
低頻度の遺伝子変異は骨のミネラル密度と骨折リスクに大きな影響を与える. ゲノム全体の配列解析で特定されたこれらの非コーディング変異は,複雑な特性の希少遺伝子変異の研究の重要性を強調しています.
科学分野:
- 遺伝学とゲノミクス
- 骨の生物学
- 骨粗鬆症 研究
背景:
- 複雑な特徴と疾患は遺伝的変異によって影響を受けますが,低頻度 (1-5%のMAF) と希少な (≤1%のMAF) 変異の寄与はほとんど不明です.
- 骨のミネラル密度 (BMD) は高度に遺伝性であり,骨粗鬆症の骨折の主要な予測因子であり,一般的なおよびまれなコーディング変異と関連しています.
- 骨髄損傷と骨折のリスクの 遺伝的構造を理解することは 効果的な予防と治療戦略の開発に不可欠です
研究 の 目的:
- 一般的なヨーロッパの祖先集団における骨格組織と骨折リスクに重大な影響を及ぼす新しい非コーディング遺伝子変異を特定する.
- 複雑な特徴の遺伝的基盤における 低頻度および希少変異の役割を調査する.
- 遺伝子研究における全ゲノムシーケンシングと高度な帰算方法の活用の根拠を提供すること.
主な方法:
- 全ゲノム配列決定 (UK10K),全エクソーム配列決定,複合参照パネルを用いた深層帰算,およびデノボ複製遺伝子型決定を用いた.
- ヨーロッパの祖先の個体におけるBMD (n=53,236) と骨折 (n=508,253) との関連性について,大規模なコホートを分析した.
- 特定された遺伝子変異の機能的影響を調査するためにマウスモデル (En1 ((cre/flox)) を使用した.
主要な成果:
- EN1遺伝子 (rs11692564(T),MAF=1. 6%) の近くで,以前報告された一般的な変異体よりも,腰椎BMDに4倍大きな効果を持つ低頻度の非コーディング変異体が見つかりました.
- このEN1変異は骨折リスクの低下 (OR=0. 85) と関連していました.
- WNT16 (rs148771817(T),MAF=1. 2%) の近くで,BMD (効果サイズ=+0. 41 s. d) に有意な影響を及ぼす別の低頻度の非コーディング変種が発見されました. ) でした.
- 有害なコード化と保存された非コード化変種からの関連信号の過剰が観察され,その重要性を示唆しています.
結論:
- 低周波の非コード変異は,骨格組織と骨折リスクに大きな影響を及ぼします.
- この発見は,複合的な特徴の遺伝的基盤を解剖するための全ゲノム配列と改良された帰算基準パネルの価値を強調しています.
- この研究は 骨の健康と骨粗鬆症の遺伝的構造を より深く理解するのに寄与しています
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