全基因组关联研究涉及脂质通路功能障碍在抗精神病药物诱导的体重增加:多祖先验证
Yundan Liao1,2,3, Hao Yu4, Yuyanan Zhang5,6,7
1Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, 100191, China.
Molecular psychiatry
|February 9, 2024
概括
抗精神病药物诱导的体重增加 (AIWG) 与新的遗传因素,PEPD和PTPRD有关. 这些参与脂质变化和2型糖尿病的基因为个性化精神分裂症治疗提供了潜在的治疗点.
科学领域:
- 药物基因组学 药物基因组学
- 代谢障碍 代谢障碍 代谢障碍
- 精神病学是一个精神病学.
背景情况:
- 抗精神病药物诱导的体重增加 (AIWG) 是一个重大的临床挑战,增加了糖尿病和心脏病的风险.
- AIWG的遗传基础仍然不完全理解,需要进一步调查.
研究的目的:
- 在汉族汉族精神分裂症患者中使用全基因组关联研究 (GWAS) 识别与AIWG相关的新型遗传位置.
- 探索脂质代谢在AIWG病变发生中的作用及其与2型糖尿病 (T2D) 的共同遗传基础.
- 使用遗传,脂质和临床因素开发AIWG的预测模型.
主要方法:
- 在汉族患者中进行两阶段GWAS,随后在欧洲队列中进行验证.
- 门德尔随机化 (MR) 分析以评估AIWG,脂质变化和T2D之间的因果关系.
- 精细映射,功能注释和多基因风险评分 (PRS) 分析.
主要成果:
- 两种新型位点,PEPD中的rs10422861和PTPRD中的rs3824417,与AIWG有显著的关联.
- 确定了PEPD和PTPRD是AIWG的潜在致病基因,在欧洲样本中验证了rs10422861.
- AIWG和T2D在PEPD中有一个共同的因果变异. 遗传预测的脂质变化 (LDL胆固醇,甘油三) 因果影响了AIWG.
- 结合脂质变化,PRS和临床因素的预测模型实现了BMI变化的高准确性 (AUC=0.79,R2=0.332).
结论:
- AIWG的致病性涉及脂质通路功能障碍,并通过PEPD基因与T2D有共同的遗传联系.
- PEPD和PTPRD代表了减轻AIWG的有希望的治疗目标.
- 这些发现支持通过整合遗传风险和代谢因素,为精神分裂症提供个性化治疗策略.
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