Holstege Henne, van der Lee Sven J, Hulsman Marc, Wong Tsz Hang, van Rooij Jeroen Gj, Weiss Marjan, Louwersheimer Eva, Wolters Frank J, Amin Najaf, Uitterlinden André G, Hofman Albert, Ikram M Arfan, van Swieten John C, Meijers-Heijboer Hanne, van der Flier Wiesje M, Reinders Marcel Jt, van Duijn Cornelia M, Scheltens Philip
Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Genetics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
Eur J Hum Genet. 2017 Aug;25(8):973-981. doi: 10.1038/ejhg.2017.87. Epub 2017 May 24.
Accumulating evidence suggests that genetic variants in the SORL1 gene are associated with Alzheimer disease (AD), but a strategy to identify which variants are pathogenic is lacking. In a discovery sample of 115 SORL1 variants detected in 1908 Dutch AD cases and controls, we identified the variant characteristics associated with SORL1 variant pathogenicity. Findings were replicated in an independent sample of 103 SORL1 variants detected in 3193 AD cases and controls. In a combined sample of the discovery and replication samples, comprising 181 unique SORL1 variants, we developed a strategy to classify SORL1 variants into five subtypes ranging from pathogenic to benign. We tested this pathogenicity screen in SORL1 variants reported in two independent published studies. SORL1 variant pathogenicity is defined by the Combined Annotation Dependent Depletion (CADD) score and the minor allele frequency (MAF) reported by the Exome Aggregation Consortium (ExAC) database. Variants predicted strongly damaging (CADD score >30), which are extremely rare (ExAC-MAF <1 × 10) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-ɛ4 allele. High-risk SORL1 variants were observed in a substantial proportion of the AD cases analyzed (2%). Based on their effect size, we propose to consider high-risk SORL1 variants next to variants in APOE, PSEN1, PSEN2 and APP for personalized risk assessments in clinical practice.
越来越多的证据表明，SORL1基因中的遗传变异与阿尔茨海默病（AD）相关，但目前缺乏一种识别哪些变异具有致病性的策略。在一个发现样本中，我们在1908例荷兰AD病例和对照中检测到115个SORL1变异，确定了与SORL1变异致病性相关的变异特征。研究结果在一个独立样本中得到重复验证，该独立样本包含在3193例AD病例和对照中检测到的103个SORL1变异。在发现样本和重复验证样本的合并样本中，包含181个独特的SORL1变异，我们制定了一种策略，将SORL1变异分为从致病性到良性的五个亚型。我们在两项独立发表的研究报告的SORL1变异中测试了这种致病性筛查方法。SORL1变异致病性由综合注释依赖损耗（CADD）评分和外显子聚合联盟（ExAC）数据库报告的次要等位基因频率（MAF）定义。预测为强损伤性（CADD评分>30）且极其罕见（ExAC-MAF<1×10）的变异使AD风险增加12倍（95%CI 4.2-34.3；P=5×10）。蛋白质截短的SORL1突变在ExAC中均未出现，且仅发生在AD病例中。更常见的SORL1变异（ExAC-MAF≥1×10）与AD风险增加无关，即使预测为强损伤性。研究结果与性别和APOE-ɛ4等位基因无关。在分析的相当一部分AD病例（2%）中观察到高风险SORL1变异。基于其效应大小，我们建议在临床实践中进行个性化风险评估时，除了考虑APOE、PSEN1、PSEN2和APP中的变异外，还要考虑高风险SORL1变异。
