Nat Commun:究竟是哪些基因变异导致我们更易得阿尔茨海默病?

2021-06-08 haibei MedSci原创

研究人员首先通过合并所有可用的病例对照数据集和代理研究结果(发现人数=409,435,验证人数=58,190)进行了一项大型的遗传关联研究。

到目前为止,除了γ-分泌酶的两个亚单位、PSEN1、PSEN2基因以及淀粉样前体蛋白基因(APP)的突变,与阿尔茨海默病(AD)相关的多个基因座已经陆续被人们所发现。最突出的基因座,即APOE,是在近30年前用连锁技术检测出来的。此外,AD病例对照数据集的全基因组关联研究(GWAS)和旁证AD病例对照研究已经确定了30个改变AD风险的基因组座。这些信号占AD遗传变异的约31%,但是,至今为止,大部分的遗传风险还没有被描述出来,而进一步探索AD常见的遗传变异,可以推动我们对AD的生物学认识,并可能鉴定出新的药物靶标。

目前,全球有超过5000万的痴呆症患者,全球痴呆症的成本远远超过1万亿美元。 这意味着在医学和经济上迫切需要有效地测试正在开发的干预措施。因此,为了增加试验的力量和缩短试验的时间,人们越来越多地关注具有高遗传疾病风险的症状前患者。然而,目前只有因果突变(APP、PSEN1和PSEN2)和APOEɛ4等位基因的携带者被认为是高风险,而其他常见和罕见的基因变异则被忽略了。尽管如此,目前已知的所有变体在多基因风险评分(PRS)中的综合影响与轻度认知障碍转化为AD、AD的神经病理学标志、发病年龄(AAO),以及AD的终身风险有关。

在最近的一项工作中,研究人员旨在理解和扩大对AD的遗传图谱的知识,并提供额外的证据,证明变体的PRS可以成为一个强大的工具,帮助人们选择具有较早AAO的高风险个体。

研究人员首先通过合并所有可用的病例对照数据集和代理研究结果(发现人数=409,435,验证人数=58,190)进行了一项大型的遗传关联研究。

阿尔茨海默病的遗传图谱

在该项研究中,研究人员增加了六个与阿尔茨海默病风险相关的变体(靠近APP、CHRNE、PRKD3/NDUFAF7、PLCG2和SHARPIN基因的两个外显子变体)。对多基因风险评分的评估和按APOE的分层显示,携带APOEɛ4的阿尔茨海默病患者发病的中位年龄有4至5.5年的差异。

基于这项研究,人们可以研究APP的基本机制,以完善对淀粉样蛋白级联的理解,该多基因风险评分也提供了一个选择阿尔茨海默病高风险个体的工具。

 

原始出处:

Itziar de Rojas et al. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nature Communications (2021). 

 

 

 

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    2021-09-10 liye789132251
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    2022-03-20 liuli5079
  4. [GetPortalCommentsPageByObjectIdResponse(id=1885218, encodeId=58041885218dc, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Fri Sep 10 01:05:58 CST 2021, time=2021-09-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817088, encodeId=4988181e088d5, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Mon Jul 05 09:05:58 CST 2021, time=2021-07-05, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2088021, encodeId=16d7208802148, content=<a href='/topic/show?id=490750196b' target=_blank style='color:#2F92EE;'>#COMMUN#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5019, encryptionId=490750196b, topicName=COMMUN)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=7931272, createdName=liuli5079, createdTime=Sun Mar 20 17:05:58 CST 2022, time=2022-03-20, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818111, encodeId=220e1818111c2, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Wed Oct 06 09:05:58 CST 2021, time=2021-10-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1314197, encodeId=0f1f131419eb4, content=<a href='/topic/show?id=b5e641e1279' target=_blank style='color:#2F92EE;'>#基因变异#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=41712, encryptionId=b5e641e1279, topicName=基因变异)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=512d422, createdName=canlab, createdTime=Thu Jun 10 05:05:58 CST 2021, time=2021-06-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1342831, encodeId=62b8134283173, content=<a href='/topic/show?id=34cb381023e' target=_blank style='color:#2F92EE;'>#变异#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=16, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=38102, encryptionId=34cb381023e, topicName=变异)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=78c32500188, createdName=12498dabm77暂无昵称, createdTime=Thu Jun 10 05:05:58 CST 2021, time=2021-06-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470465, encodeId=1b2d14e046540, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=17, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c5917090900, createdName=yhj-time, createdTime=Thu Jun 10 05:05:58 CST 2021, time=2021-06-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=972148, encodeId=cf6f9e21481e, content=谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=46, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20210608/f68c5332fff04294b99141d8b88d3ec2/a494511dd06348b7a3b1343acc4c272c.jpg, createdBy=77075513887, createdName=坦坦ms5000001437056934, createdTime=Wed Jun 09 14:47:48 CST 2021, time=2021-06-09, status=1, ipAttribution=)]
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    2021-06-09 坦坦ms5000001437056934

    谢谢

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