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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567154/
https://www.ncbi.nlm.nih.gov/pubmed/28537274
http://dx.doi.org/10.1038/ejhg.2017.87
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author 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
author_facet 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
author_sort Holstege, Henne
collection PubMed
description 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-ε4 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.
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spelling pubmed-55671542017-08-29 Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy 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 Eur J Hum Genet Article 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-ε4 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. Nature Publishing Group 2017-08 2017-05-24 /pmc/articles/PMC5567154/ /pubmed/28537274 http://dx.doi.org/10.1038/ejhg.2017.87 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-sa/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Article
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
Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title_full Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title_fullStr Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title_full_unstemmed Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title_short Characterization of pathogenic SORL1 genetic variants for association with Alzheimer’s disease: a clinical interpretation strategy
title_sort characterization of pathogenic sorl1 genetic variants for association with alzheimer’s disease: a clinical interpretation strategy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567154/
https://www.ncbi.nlm.nih.gov/pubmed/28537274
http://dx.doi.org/10.1038/ejhg.2017.87
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