Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.
Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease.
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DOI：
10.3233/jad-150749
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发表时间：
2016-06-18
期刊：
影响因子：
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通讯作者：
International Genomics of Alzheimer’s Project
中科院分区：
文献类型：
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作者：
Chouraki V;Reitz C;Maury F;Bis JC;Bellenguez C;Yu L;Jakobsdottir J;Mukherjee S;Adams HH;Choi SH;Larson EB;Fitzpatrick A;Uitterlinden AG;de Jager PL;Hofman A;Gudnason V;Vardarajan B;Ibrahim-Verbaas C;van der Lee SJ;Lopez O;Dartigues JF;Berr C;Amouyel P;Bennett DA;van Duijn C;DeStefano AL;Launer LJ;Ikram MA;Crane PK;Lambert JC;Mayeux R;Seshadri S;International Genomics of Alzheimer’s Project
有效预防阿尔茨海默病（AD）需要开发允许临床前干预的风险预测工具。我们构建了一个遗传风险评分（GRS），包括与AD相关的常见遗传变异，评估其与AD事件的相关性，并评估其在基于年龄，性别，教育和APOE ε4的传统模型上改善风险预测的能力。在国际阿尔茨海默病基因组学项目（IGAP）中包含的8个前瞻性队列中，我们从IGAP GWAS报告的65岁及以上未患痴呆症的参与者中的19个顶级SNP中推导出风险等位基因的加权总和。在考克斯模型中估计AD事件的风险比（HR）。风险预测的改善通过C指数差异（Δ-C）、综合区分改善（IDI）和连续净重新分类改善（NRI>0）来衡量。总体而言，19，687名有风险的参与者被纳入其中，其中2，782人发展为AD。GRS与AD风险增加17%相关（合并HR = 1.17; 95%CI = [1.13-1.21]/GRS标准差增加; p值= 2.86 × 10−16）。这种关联在至少有一个APOE ε4等位基因的人群中（HRGRS = 1.24; 95%CI = [1.15-1.34]）比其他人群（HRGRS = 1.13; 95%CI = [1.08-1.18]; pinteraction = 3.45 × 10−2）更强。7年随访后的风险预测显示，当将GRS与年龄、性别、APOE ε4和教育程度相加时，风险预测略有改善（Δ-Cindex = 0.0043 [0.0019-0.0067]）。对于IDI和NRI>0，观察到类似的模式。总之，结合APOE ε4基因座以外的常见遗传变异的风险评分改善了AD风险预测，并可能有助于预防试验的风险分层。
Effective prevention of Alzheimer’s disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOE ε4. In eight prospective cohorts included in the International Genomics of Alzheimer’s Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ–C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95%CI = [1.13–1.21] per standard deviation increase in GRS; p-value = 2.86 × 10−16). This association was stronger among persons with at least one APOE ε4 allele (HRGRS = 1.24; 95%CI = [1.15–1.34]) than in others (HRGRS = 1.13; 95%CI = [1.08–1.18]; pinteraction = 3.45 × 10−2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOE ε4, and education (Δ–Cindex = 0.0043 [0.0019–0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOE ε4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.