脑龄差异的遗传风险位点及与14种脑部疾病的因果关系分析  

Genetic risk loci for brain age gap and the analysis of causal relationship with 14 brain diseases

作　　者：彭凯 易帆 张岁霞 王凯[3] 黄正行[2] Peng Kai;Yi Fan;Zhang Suixia;Wang Kai;Huang Zhengxing(College of Public Health,Xinjiang Medical University,Urumqi 830054,China;Zhejiang University,Hangzhou 310058,China;College of Medical Engineering Technology,Xinjiang Medical University,Urumqi 830054,China)

机构地区：[1]新疆医科大学公共卫生学院,乌鲁木齐830054 [2]浙江大学,杭州310058 [3]新疆医科大学医学工程技术学院,乌鲁木齐830054

出　　处：《中华精神科杂志》2024年第3期164-175,共12页Chinese Journal of Psychiatry

基　　金：新疆维吾尔自治区重大科技专项项目(2022A03019-1);省部共建中亚高发病成因与防治国家重点实验室开放课题(SKL-HIDCA-2022-23);新疆维吾尔自治区自然科学基金资助项目(2021D01C295)。

摘　　要：目的探讨脑龄差异(brain age gap,BAG)作为大脑健康生物标志物的潜力及其与常见脑部疾病的因果关系。方法选取公共数据库英国生物银行(UK Biobank,UKB)、阿尔茨海默病神经影像学倡议(Alzheimer′s Disease Neuroimaging Initiative,ADNI)、帕金森病进展标志物倡议(Parkinson′s Progression Markers Initiative,PPMI)数据库中脑部结构磁共振成像(structural magnetic resonance imaging,sMRI)图像,输入简单全卷积神经网络(simple fully convolutional network,SFCN)估计脑龄差异;根据有无ICD-10编码和相应脑部疾病标签定义患者组(有相应编码或标签,n=6796)和健康对照组(无相应编码或标签,n=9660),采用双样本t检验比较患者组和健康对照组脑龄差异;使用全基因组关联分析(genome-wide association study,GWAS)分析UKB数据库31520人中与脑龄差异显著相关基因组区域;通过孟德尔随机化(mendelian randomization,MR)分析脑龄差异与14种脑部疾病之间的因果效应。结果健康对照组中用于测试的受试者(n=1932)的实际年龄与估计脑龄之间平均绝对误差为2.364岁;与健康对照组相比,患者组中阿尔茨海默病(t=33.42)、焦虑障碍(t=2.38)、双相障碍(t=3.76)、脑卒中(t=2.75)、脱髓鞘疾病(t=7.45)、抑郁症(t=3.49)、帕金森病(t=17.69)、创伤后应激障碍(t=2.34)脑龄差异显著增加(PFDR<0.05);在GWAS中有8个与脑龄差异相关的独立全基因组风险位点(P<5×10-8),其中4个是新发现的(相关基因:PICK1、TBC1D9、SIAH3、TMEM98);MR分析显示阿尔茨海默病与脑龄差异之间存在强因果关系(β=0.23,95%CI=0.08~0.38,PFDR=0.030)。结论脑龄差异可作为反映大脑健康信息的生物标志物,同时阿尔茨海默病的发生会导致脑龄差异增加。Objective To explore the potential of brain age gap(BAG)as a biomarker of brain health and analyze its causal relationship with common brain diseases.Methods Brain structural magnetic resonance imaging(sMRI)data from public databases(UK Biobank,ADNI,PPMI)were selected and input into a simple fully convolutional network(SFCN)to estimate BAG.The disease group(with corresponding codes or labels,n=6796)and healthy control group(without corresponding codes or labels,n=9660)were defined according to the presence or absence of ICD-10 codes and corresponding brain disease labels.The two-sample t-test was used to compare the BAG differences between the disease and healthy control group;genome-wide association study(GWAS)was used to find genomic regions significantly associated with BAG in 31520 people in the UK Biobank.The causal effects between BAG and 14 brain diseases were analyzed by Mendelian randomization(MR).Results The mean absolute error(MAE)between the subject′s chronological age and estimated brain age for the 1932 subjects in the healthy control group used for model testing was 2.364 years.Compared with the healthy control group,Alzheimer′s disease(t=33.42),anxiety disorders(t=2.38),bipolar disorder(t=3.76),stroke(t=2.75),demyelinating disease(t=7.45),major depressive disorder(t=3.49),Parkinson′s disease(t=17.69),and post-traumatic stress disorder(t=2.34)BAG was significantly increased(PFDR<0.05).There were 8 independent genome-wide risk regions associated with BAG in the GWAS(P<5×10-8),4 of which were novel(related genes:PICK1,TBC1D9,SIAH3,and TMEM98).In MR analysis,a strong causal association between Alzheimer′s disease and BAG was observed(β=0.23,95%CI=0.08-0.38,PFDR=0.030).Conclusion BAG can be used as a biomarker that reflects brain health information.The occurrence of Alzheimer′s disease will lead to an increase in BAG.

关 键 词：生物学标记 脑龄差异 全基因组关联分析 孟德尔随机化分析 

分 类 号：R742[医药卫生—神经病学与精神病学]