| Title: | Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk |
| Journal: | American Journal of Human Genetics |
| Published: | 26 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42648288/ |
| DOI: | https://doi.org/10.1016/j.ajhg.2026.07.013 |
Publication 20888
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Abstract
Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10-7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.</p>
120 Authors
- Olivier Quenez
- Catherine Schramm
- Kévin Cassinari
- Aude Nicolas
- Joan Groeneveld
- Guillaume Huguet
- Benjamin Grenier-Boley
- Marc Hulsman
- G. Bragi Walters
- Itziar de Rojas
- Anne Rovelet-Lecrux
- Sébastien Feuillette
- Laetitia Miguel
- Anne-Claire Richard
- Stéphane Rousseau
- Shahzad Ahmad
- Najaf Amin
- Philippe Amouyel
- Olivia Belbin
- Céline Bellenguez
- Claudine Berr
- Paola Bossù
- Femke Bouwman
- Jose Bras
- Jordi Clarimon
- Antonio Daniele
- Jean-François Dartigues
- Stéphanie Debette
- Jean-François Deleuze
- Nicola Denning
- Oriol Dols-Icardo
- Cornelia M. van Duijn
- Juan Fortea
- Nick C. Fox
- Ruth Frikke-Schmidt
- Daniela Galimberti
- Roberta Ghidoni
- Vilmantas Giedraitis
- Johan J.P. Gille
- Detelina Grozeva
- Rita Guerreiro
- Edna Grünblatt
- John Hardy
- Steffi G. Riedel-Heller
- Mikko Hiltunen
- Clive Holmes
- Jakub Hort
- Holger Hummerich
- M. Arfan Ikram
- M. Kamran Ikram
- Martin Ingelsson
- Iris E. Jansen
- Amit Kawalia
- Robert Kraaij
- Patrick G. Kehoe
- Marc Lathrop
- Morgane Lacour
- Afina W. Lemstra
- Alberto Lleó
- Lauren Luckcuck
- Marcel M.A.M. Mannens
- Rachel Marshall
- Carlo Masullo
- Simon Mead
- Patrizia Mecocci
- Alexandre de Mendonça
- Alun Meggy
- Shima Mehrabian
- Merel O. Mol
- Kevin Morgan
- Alexandre Morin
- Benedetta Nacmias
- Penny J. Norsworthy
- Robert Olaso
- Florence Pasquier
- Pau Pastor
- Fabrizio Piras
- Julius Popp
- Alfredo Ramirez
- Rachel Raybould
- Richard Redon
- Marcel J.T. Reinders
- Fernando Rivadeneira
- Jeroen G.J. van Rooij
- Natalie S. Ryan
- Salha Saad
- Pascual Sanchez-Juan
- Nikolaos Scarmeas
- Philip Scheltens
- Jonathan M. Schott
- Davide Seripa
- Daoud Sie
- Rebecca Sims
- Erik A. Sistermans
- Sandro Sorbi
- Kristel Sleegers
- Resie van Spaendonk
- John C. van Swieten
- Niccolo' Tesi
- Betty M. Tijms
- Magda Tsolaki
- André G. Uitterlinden
- Jort Vijverberg
- Pieter Jelle Visser
- Michael Wagner
- Julie Williams
- Aline Zarea
- EADB Consortium
- Emmanuelle Génin
- Henne Holstege
- Daniel F. Gudbjartsson
- David Wallon
- Magalie Lecourtois
- Maria Victoria Fernandez
- Hreinn Stefansson
- Sébastien Jacquemont
- Jean-Charles Lambert
- Sven J. van der Lee
- Camille Charbonnier
- Gaël Nicolas
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