Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins.
Measuring heritable contributions to Alzheimer's disease: polygenic risk score analysis with twins.
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DOI：
10.1093/braincomms/fcab308
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发表时间：
2022
影响因子：
4.8
通讯作者：
Reynolds CA
中科院分区：
文献类型：
--
作者：
Karlsson IK;Escott-Price V;Gatz M;Hardy J;Pedersen NL;Shoai M;Reynolds CA
从双胞胎研究中估计的阿尔茨海默病的遗传力高于基于基因组的研究得出的遗传力，其原因尚不清楚。我们将这两种方法应用于同一个双胞胎样本，考虑阿尔茨海默病多基因风险评分和双胞胎模型的遗传力，以深入了解测量的遗传变异的作用并量化未捕获的遗传风险。 1986 年至 2016 年间进行了一项基于人群的阿尔茨海默病遗传性和多基因关联研究，这是第一项将多基因风险评分纳入阿尔茨海默病生物特征双胞胎模型的研究。样本包括从瑞典双胞胎登记处抽取的 1586 对双胞胎，这些双胞胎嵌套在 1137 对双胞胎中（449 对完整对和 688 对不完整对），并进行了基于临床的诊断和登记随访（Mage = 85.28，SD = 7.02；44% 男性；431 例病例和 1155 例对照）。考虑到完整的多基因风险评分（PRS）、没有 APOE 区域的 PRS（PRS.no.APOE）和 PRS.no.APOE 加上直接测量的 APOE 等位基因，我们报告了 P < 1 × 10−5 的多基因风险评分的贡献。生物识别双胞胎模型估计了环境影响以及已测量（PRS）和未测量基因对阿尔茨海默病风险的影响。完整的 PRS 和 PRS.no.APOE 分别对阿尔茨海默病风险造成 10.1% 和 2.4%。当 APOE ɛ4 等位基因与 PRS.no.APOE 一起添加到模型中时，对阿尔茨海默病风险的总贡献为 11.4%，其中 APOE ɛ4 解释了 9.3%，PRS.no.APOE 从 2.4% 下降到 2.1%。遗传对阿尔茨海默病风险的总影响（测量和未测量）为 71%，而每对双胞胎特有的环境影响占风险的 29%。 APOE 区域对阿尔茨海默病的可测量遗传贡献很大，其他可测量的多基因影响的贡献较小。重要的是，实质性的背景遗传影响仍有待了解。卡尔森等人。报告测量了基于基因组的研究的多基因评分，包括 APOE 的巨大作用，只能解释阿尔茨海默病双胞胎模型所表明的遗传性的一小部分，而导致阿尔茨海默病的大多数遗传风险无法解释。需要灵敏的设计来捕获所有遗传影响。
The heritability of Alzheimer’s disease estimated from twin studies is greater than the heritability derived from genome-based studies, for reasons that remain unclear. We apply both approaches to the same twin sample, considering both Alzheimer’s disease polygenic risk scores and heritability from twin models, to provide insight into the role of measured genetic variants and to quantify uncaptured genetic risk. A population-based heritability and polygenic association study of Alzheimer’s disease was conducted between 1986 and 2016 and is the first study to incorporate polygenic risk scores into biometrical twin models of Alzheimer’s disease. The sample included 1586 twins drawn from the Swedish Twin Registry which were nested within 1137 twin pairs (449 complete pairs and 688 incomplete pairs) with clinically based diagnoses and registry follow-up (Mage = 85.28, SD = 7.02; 44% male; 431 cases and 1155 controls). We report contributions of polygenic risk scores at P < 1 × 10−5, considering a full polygenic risk score (PRS), PRS without the APOE region (PRS.no.APOE) and PRS.no.APOE plus directly measured APOE alleles. Biometric twin models estimated the contribution of environmental influences and measured (PRS) and unmeasured genes to Alzheimer’s disease risk. The full PRS and PRS.no.APOE contributed 10.1 and 2.4% to Alzheimer’s disease risk, respectively. When APOE ɛ4 alleles were added to the model with the PRS.no.APOE, the total contribution was 11.4% to Alzheimer’s disease risk, where APOE ɛ4 explained 9.3% and PRS.no.APOE dropped from 2.4 to 2.1%. The total genetic contribution to Alzheimer’s disease risk, measured and unmeasured, was 71% while environmental influences unique to each twin accounted for 29% of the risk. The APOE region accounts for much of the measurable genetic contribution to Alzheimer’s disease, with a smaller contribution from other measured polygenic influences. Importantly, substantial background genetic influences remain to be understood. Karlsson et al. report that measured polygenic scores from genome-based studies, including an outsized role for APOE, explain only a fraction of the heritability indicated by twin models of Alzheimer’s disease, leaving most genetic risk for Alzheimer’s disease unexplained. Sensitive designs are needed to capture all the genetic influences.
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影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
1.9
作者：
Finkel, D;Pedersen, NL
通讯作者：
Pedersen, NL
影响因子：
4.2
作者：
Escott-Price, Valentina;Shoai, Maryam;Hardy, John
通讯作者：
Hardy, John
影响因子：
30.8
作者：
Mancuso N;Rohland N;Rand KA;Tandon A;Allen A;Quinque D;Mallick S;Li H;Stram A;Sheng X;Kote-Jarai Z;Easton DF;Eeles RA;PRACTICAL consortium;Le Marchand L;Lubwama A;Stram D;Watya S;Conti DV;Henderson B;Haiman CA;Pasaniuc B;Reich D
通讯作者：
Reich D
DOI：
10.3233/jad-191192
发表时间：
2020
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Beam CR;Kaneshiro C;Jang JY;Reynolds CA;Pedersen NL;Gatz M
通讯作者：
Gatz M