Journal Article

DZNE-2026-01019

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.

Quenez, O. ; Schramm, C. ; Cassinari, K. ; Nicolas, A. ; Groeneveld, J. ; Huguet, G. ; Grenier-Boley, B. ; Hulsman, M. ; Walters, G. B. ; de Rojas, I. ; Rovelet-Lecrux, A. ; Feuillette, S. ; Miguel, L. ; Richard, A.-C. ; Rousseau, S. ; Ahmad, S. ; Amin, N. ; Amouyel, P. ; Belbin, O. ; Bellenguez, C. ; Berr, C. ; Bossù, P. ; Bouwman, F. ; Bras, J. ; Clarimon, J. ; Daniele, A. ; Dartigues, J.-F. ; Debette, S. ; Deleuze, J.-F. ; Denning, N. ; Dols-Icardo, O. ; van Duijn, C. M. ; Fortea, J. ; Fox, N. C. ; Frikke-Schmidt, R. ; Galimberti, D. ; Ghidoni, R. ; Giedraitis, V. ; Gille, J. J. P. ; Grozeva, D. ; Guerreiro, R. ; Grünblatt, E. ; Hardy, J. ; Riedel-Heller, S. G. ; Hiltunen, M. ; Holmes, C. ; Hort, J. ; Hummerich, H. ; Ikram, M. A. ; Ikram, M. K. ; Ingelsson, M. ; Jansen, I. E. ; Kawalia, A. ; Kraaij, R. ; Kehoe, P. G. ; Lathrop, M. ; Lacour, M. ; Lemstra, A. W. ; Lleó, A. ; Luckcuck, L. ; Mannens, M. M. A. M. ; Marshall, R. ; Masullo, C. ; Mead, S. ; Mecocci, P. ; de Mendonça, A. ; Meggy, A. ; Mehrabian, S. ; Mol, M. O. ; Morgan, K. ; Morin, A. ; Nacmias, B. ; Norsworthy, P. J. ; Olaso, R. ; Pasquier, F. ; Pastor, P. ; Piras, F. ; Popp, J. ; Ramirez, A.DZNE* ; Raybould, R. ; Redon, R. ; Reinders, M. J. T. ; Rivadeneira, F. ; van Rooij, J. G. J. ; Ryan, N. S. ; Saad, S. ; Sanchez-Juan, P. ; Scarmeas, N. ; Scheltens, P. ; Schott, J. M. ; Seripa, D. ; Sie, D. ; Sims, R. ; Sistermans, E. A. ; Sorbi, S. ; Sleegers, K. ; van Spaendonk, R. ; van Swieten, J. C. ; Tesi, N. ; Tijms, B. M. ; Tsolaki, M. ; Uitterlinden, A. G. ; Vijverberg, J. ; Visser, P. J. ; Wagner, M.DZNE* ; Williams, J. ; Zarea, A. ; Consortium, E. (Collaboration Author) ; Génin, E. ; Holstege, H. ; Gudbjartsson, D. F. ; Wallon, D. ; Lecourtois, M. ; Fernandez, M. V. ; Stefansson, H. ; Jacquemont, S. ; Lambert, J.-C. ; van der Lee, S. J. ; Charbonnier, C. ; Nicolas, G.

2026
Cell Press New York, NY [u.a.]

This record in other databases:    

Please use a persistent id in citations: doi:10.1016/j.ajhg.2026.07.013

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.

Keyword(s): Humans (MeSH) ; DNA Copy Number Variations: genetics (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Exome: genetics (MeSH) ; Chromosomes, Human, Pair 22: genetics (MeSH) ; Female (MeSH) ; Aged (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Gene Dosage (MeSH) ; Male (MeSH) ; Exome Sequencing (MeSH) ; 22q11 ; Alzheimer disease ; association study ; burden ; copy-number variant ; deletion ; duplication

---

Contributing Institute(s):

1. Patient Studies (Bonn) (Patient Studies (Bonn))
2. Neuropsychology (AG Wagner)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

---

Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---