The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD.

中文翻译：

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对欧洲早发阿尔茨海默氏病中SORL1稀有变异的遗传影响的综合研究。

与sortilin相关的受体1（SORL1）基因与阿尔茨海默氏病（AD）的风险增加有关。SORL1基因中的罕见遗传变异也与常染色体显性遗传早期AD（EOAD）有关。在这里，我们报告了欧洲EOAD队列中SORL1对EOAD的遗传变异性贡献的大规模调查。在欧洲早发性痴呆（EOD）联盟的背景下，我们对1255名EOAD患者和1938个年龄和起源匹配的对照个体中的SORL1的完整编码区进行了大规模的基于扩增子的并行重测序。西班牙，葡萄牙，意大利，瑞典，德国和捷克共和国。我们确定了仅在患者中存在的六个移码变体和两个废话变体。预测这些突变将通过无义介导的mRNA衰变而导致单倍体功能不足，这可以通过对比利时EOAD患者中观察到的SORL1 p.Gly447Argfs * 22进行实验证实。我们观察到患者中罕见的非同义变体的富集程度达到1.5倍（载波频率8.8％； SkatOMeta p值0.0001）。在整个患者/对照队列中检测到的84个非同义词稀有变体中，仅在患者中检测到了36个。我们的发现强调了稀有的SORL1变体在EOAD中的作用，但也表明这些变体在健康个体中的频率不可忽略，因此需要进行病原性测定。迄今为止，仅在患者中发现了由于移码和无意义的变异而导致的提前终止密码子，