Normandie Université, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNRMAJ, FHU-G4 Génomique, 22 boulevard Gambetta - CS 76183, Rouen, F-76000, France.
Normandie Université, UNIROUEN, Inserm U1245, CHU Rouen, Department of Neurology and CNRMAJ, FHU-G4 Génomique, Rouen, F-76000, France.
Genome Med. 2022 Jun 28;14(1):69. doi: 10.1186/s13073-022-01070-6.
Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE-ε4, make such estimations difficult.
We proposed to estimate the age-related penetrance of SORL1-LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1-LoF variants, stratified by APOE-ε4, derived from the Rotterdam study (N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1-LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE-ε4-stratified SORL1-LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia.
SORL1-LoF variants penetrance curves reached 100% (95% confidence interval [99-100%]) by age 70 among APOE-ε4ε4 carriers only, compared with 56% [40-72%] and 37% [26-51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1-LoF variant carriers in case-control study data.
We conclude that SORL1-LoF variants should be interpreted in light of APOE genotypes for future clinical applications.
阿尔茨海默病（AD）是一种常见的复杂疾病，具有很高的遗传成分。功能丧失（LoF）SORL1 变体是 AD 最强的遗传风险因素之一。在潜在用于遗传咨询或预防试验之前，估计其与年龄相关的外显率至关重要。然而，由于相对罕见性以及与主要 AD 风险因素 APOE-ε4 的共存，使得这种估计变得困难。
我们通过生存框架提出了一种估计 SORL1-LoF 变体与年龄相关的外显率的方法，通过估计结合（i）非 SORL1-LoF 变体携带者的基线风险，按 APOE-ε4 分层，该基线来自鹿特丹研究（N=12255），以及（ii）从法国年轻阿尔茨海默病患者参考中心招募的 27 个扩展家系（包括 307 名≥40 岁的亲属，其中 45 名有基因分型信息）中估计的 SORL1-LoF 变体的年龄依赖性比例风险效应。我们将该模型嵌入到期望最大化算法中，以适应缺失的基因型。为了纠正确定偏差，省略了先证者的表型。然后，我们评估了我们的外显率曲线是否与从欧洲和美国病例对照研究联盟的 13007 例病例和 10182 例对照的测序数据中检测到的按 APOE-ε4 分层的 SORL1-LoF 变体携带者的年龄分布一致。
在 APOE-ε4ε4 携带者中，SORL1-LoF 变体的外显率曲线在 70 岁时达到 100%（99-100%），而在ε4 杂合携带者和ε4 非携带者中，分别为 56%[40-72%]和 37%[26-51%]。这些估计与病例对照研究数据中 SORL1-LoF 变体携带者的实际年龄分布完全一致。
我们的结论是，在进行未来的临床应用时，应根据 APOE 基因型来解释 SORL1-LoF 变体。
