Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease

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

Holstege, H. (TU Delft Pattern Recognition and Bioinformatics; Amsterdam UMC)
van der Lee, S.J. (TU Delft Pattern Recognition and Bioinformatics; Amsterdam UMC)
Hulsman, M. (TU Delft Pattern Recognition and Bioinformatics; Amsterdam UMC)
Hang Wong, Tsz (Erasmus MC)
van Rooij, Jeroen G.J. (Erasmus MC)
Weiss, Marjan (Amsterdam UMC)
Louwersheimer, Eva (Amsterdam UMC)
Wolters, Frank J, (Erasmus MC)
Amin, Najaf (Erasmus MC)
Reinders, M.J.T. (TU Delft Pattern Recognition and Bioinformatics)

2017

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.

Alzheimer's disease
Diagnostic markers
Genetics research

http://resolver.tudelft.nl/uuid:78e36fea-7db8-4b01-8dbb-9ba42f8c8f24

https://doi.org/10.1038/ejhg.2017.87

1018-4813

European Journal of Human Genetics, 25 (8), 973-981

Institutional Repository

journal article

© 2017 H. Holstege, S.J. van der Lee, M. Hulsman, Tsz Hang Wong, Jeroen G.J. van Rooij, Marjan Weiss, Eva Louwersheimer, Frank J, Wolters, Najaf Amin, M.J.T. Reinders, More Authors