ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.
ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.
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DOI：
10.1212/nxg.0000000000000079
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Alzheimer's Disease Genetics Consortium
中科院分区：
文献类型：
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作者：
Cukier HN;Kunkle BW;Vardarajan BN;Rolati S;Hamilton-Nelson KL;Kohli MA;Whitehead PL;Dombroski BA;Van Booven D;Lang R;Dykxhoorn DM;Farrer LA;Cuccaro ML;Vance JM;Gilbert JR;Beecham GW;Martin ER;Carney RM;Mayeux R;Schellenberg GD;Byrd GS;Haines JL;Pericak-Vance MA;Alzheimer's Disease Genetics Consortium
目的：在晚发性阿尔茨海默病(AD)的已知危险因素--三磷酸腺苷结合盒A亚家族A(Abc1)，成员7(Abca7)基因中发现一个可能导致非裔美国人阿尔茨海默病(AD)的致病变异(S)。对40例再生障碍性贫血患者和37例携带再生障碍性贫血风险等位基因(Rs115550680)的∼进行150kb的定制捕获测序。对大型AA数据集(发现n=1,068；复制n=1,749)中发现的ABCA7缺失和加勒比拉美裔(CH)AD家族的整个外显子组测序进行关联测试。在所有77个风险基因携带者中均检测到44碱基缺失(Rs142076058)，表明该缺失与风险等位基因处于高度连锁不平衡状态。在一个大型数据集(531个病例和527个对照)中对缺失进行了评估，在调整了年龄、性别和载脂蛋白E状态后，该缺失与疾病显著相关(p=0.0002，优势比[OR]=2.13[95%可信区间：1.42-3.2])。一个独立的数据集重复了这种关联(447例和880名对照，p=0.0117，OR=1.65[95%CI：1.12-2.44])，联合分析增加了显著性(p=1.414×10−5，OR=1.81[95%CI：1.38-2.37])。缺失在再生障碍性贫血患者(15.2%)和再生障碍性贫血对照组(9.74%)中很常见，但在我们的非西班牙裔白人队列中只有0.12%。对多个CH家系进行外显子全序列测序，在一个较大的兄弟姐妹中发现了与疾病相关的缺失。缺失的等位基因产生稳定的、可检测到的RNA链，并被预测会导致可能干扰蛋白质功能的移码突变(p.Arg578Alafs)。这种常见的ABCA7缺失可能代表了阿尔茨海默病的种族特异性致病改变。
To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.