Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: A clinical interpretation strategy

Henne Holstege, Sven J. Van Der Lee, Marc Hulsman, Tsz Hang Wong, Jeroen G.J. Van Rooij, Marjan Weiss, Eva Louwersheimer, Frank J. Wolters, Najaf Amin, André G. Uitterlinden, Albert Hofman, M. Arfan Ikram, John C. Van Swieten, Hanne Meijers-Heijboer, Wiesje M. Van Der Flier, Marcel J.T. Reinders, Cornelia M. Van Duijn, Philip Scheltens

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72 Citations (Scopus)


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 '5) increased AD risk by 12-fold (95% CI 4.2-34.3; P=5 × 10 '9). Protein-truncating SORL1 mutations were all unknown to ExAC and occurred exclusively in AD cases. More common SORL1 variants (ExAC-MAF≥1 × 10 '5) were not associated with increased AD risk, even when predicted strongly damaging. Findings were independent of gender and the APOE-I 4 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.

Original languageEnglish
Pages (from-to)973-981
Number of pages9
JournalEuropean journal of human genetics
Issue number8
Publication statusPublished - 1 Aug 2017

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