Scholarlink

Background <p>Protein truncating variants (PTVs) in <i>SORL1</i> are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare <i>SORL1</i> missense variants is unclear.</p> Methods <p>To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding <i>SORL1</i> variants detected in 18,959 AD-cases and 21,893 non-demented controls.</p> Results <p>In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and <i>APOE</i>-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type <i>SORL1</i> carriers, matched for <i>APOE</i>-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.</p> Conclusion <p>Our results justify a debate on whether HPV carriers should be considered for clinical counseling.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月1日

查看全文
  • Olav M. Andersen,
  • Matthijs W. J. de Waal,
  • Giulia Monti,
  • Niccolo Tesi,
  • Anne Mette G. Jensen,
  • Christa de Geus,
  • Rosalina van Spaendonk,
  • Maartje Vogel,
  • Shahzad Ahmad,
  • Najaf Amin,
  • Philippe Amouyel,
  • Gary W. Beecham,
  • Céline Bellenguez,
  • Claudine Berr,
  • Joshua C. Bis,
  • Anne Boland,
  • Paola Bossù,
  • Femke Bouwman,
  • Jose Bras,
  • Camille Charbonnier,
  • Jordi Clarimon,
  • Carlos Cruchaga,
  • Antonio Daniele,
  • Jean-François Dartigues,
  • Stéphanie Debette,
  • Jean-François Deleuze,
  • Nicola Denning,
  • Anita L. DeStefano,
  • Oriol Dols-Icardo,
  • Cornelia M. van Duijn,
  • Lindsay A. Farrer,
  • Maria Victoria Fernández,
  • Wiesje M. van der Flier,
  • Nick C. Fox,
  • Daniela Galimberti,
  • Emmanuelle Genin,
  • Johan J. P. Gille,
  • Benjamin Grenier-Boley,
  • Detelina Grozeva,
  • Yann Le Guen,
  • Rita Guerreiro,
  • Jonathan L. Haines,
  • Clive Holmes,
  • Holger Hummerich,
  • M. Arfan Ikram,
  • M. Kamran Ikram,
  • Amit Kawalia,
  • Robert Kraaij,
  • Jean-Charles Lambert,
  • Marc Lathrop,
  • Afina W. Lemstra,
  • Alberto Lleó,
  • Richard M. Myers,
  • Marcel M. A. M. Mannens,
  • Rachel Marshall,
  • Eden R. Martin,
  • Carlo Masullo,
  • Richard Mayeux,
  • Simon Mead,
  • Patrizia Mecocci,
  • Alun Meggy,
  • Merel O. Mol,
  • Benedetta Nacmias,
  • Adam C. Naj,
  • Valerio Napolioni,
  • J. Nicholas Cochran,
  • Gaël Nicolas,
  • Florence Pasquier,
  • Pau Pastor,
  • Margaret A. Pericak-Vance,
  • Yolande A. L. Pijnenburg,
  • Fabrizio Piras,
  • Olivier Quenez,
  • Alfredo Ramirez,
  • Rachel Raybould,
  • Richard Redon,
  • Marcel J. T. Reinders,
  • Anne-Claire Richard,
  • Steffi G. Riedel-Heller,
  • Fernando Rivadeneira,
  • Jeroen G. J. van Rooij,
  • Stéphane Rousseau,
  • Natalie S. Ryan,
  • Pascual Sanchez-Juan,
  • Gerard D. Schellenberg,
  • Philip Scheltens,
  • Jonathan M. Schott,
  • Sudha Seshadri,
  • Daoud Sie,
  • Rebecca Sims,
  • Erik A. Sistermans,
  • Sandro Sorbi,
  • John C. van Swieten,
  • Betty Tijms,
  • André G. Uitterlinden,
  • Pieter Jelle Visser,
  • Michael Wagner,
  • David Wallon,
  • Li-San Wang,
  • Julie Williams,
  • Jennifer S. Yokoyama,
  • Aline Zarea,
  • Sven J. van der Lee,
  • Johan G. Olsen,
  • Marc Hulsman,
  • Henne Holstege

摘要

Background

Protein truncating variants (PTVs) in SORL1 are observed almost exclusively in Alzheimer’s Disease (AD) cases, but the effect of rare SORL1 missense variants is unclear.

Methods

To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding SORL1 variants detected in 18,959 AD-cases and 21,893 non-demented controls.

Results

In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and APOE-genotype contributed to AAO-variability. The median AAO of PTV- and HPV-carriers is ~8–10 years earlier than wild-type SORL1 carriers, matched for APOE-genotype. Specific HPVs are highly penetrant and lead to earlier AAOs than PTVs, suggesting possible dominant negative effects.

Conclusion

Our results justify a debate on whether HPV carriers should be considered for clinical counseling.