American journal of human genetics · 2026

Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.

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Quenez Olivier, Schramm Catherine, Cassinari Kévin, Nicolas Aude, Groeneveld Joan, Huguet Guillaume, Grenier-Boley Benjamin, Hulsman Marc, Walters G Bragi, de Rojas Itziar, Rovelet-Lecrux Anne, Feuillette Sébastien, Miguel Laetitia, Richard Anne-Claire, Rousseau Stéphane, Ahmad Shahzad, Amin Najaf, Amouyel Philippe, Belbin Olivia, Bellenguez Céline, Berr Claudine, Bossù Paola, Bouwman Femke, Bras Jose, Clarimon Jordi, Daniele Antonio, Dartigues Jean-François, Debette Stéphanie, Deleuze Jean-François, Denning Nicola, Dols-Icardo Oriol, van Duijn Cornelia M, Fortea Juan, Fox Nick C, Frikke-Schmidt Ruth, Galimberti Daniela, Ghidoni Roberta, Giedraitis Vilmantas, Gille Johan J P, Grozeva Detelina, Guerreiro Rita, Grünblatt Edna, Hardy John, Riedel-Heller Steffi G, Hiltunen Mikko, Holmes Clive, Hort Jakub, Hummerich Holger, Ikram M Arfan, Ikram M Kamran, Ingelsson Martin, Jansen Iris E, Kawalia Amit, Kraaij Robert, Kehoe Patrick G, Lathrop Marc, Lacour Morgane, Lemstra Afina W, Lleó Alberto, Luckcuck Lauren, Mannens Marcel M A M, Marshall Rachel, Masullo Carlo, Mead Simon, Mecocci Patrizia, de Mendonça Alexandre, Meggy Alun, Mehrabian Shima, Mol Merel O, Morgan Kevin, Morin Alexandre, Nacmias Benedetta, Norsworthy Penny J, Olaso Robert, Pasquier Florence, Pastor Pau, Piras Fabrizio, Popp Julius, Ramirez Alfredo, Raybould Rachel, Redon Richard, Reinders Marcel J T, Rivadeneira Fernando, van Rooij Jeroen G J, Ryan Natalie S, Saad Salha, Sanchez-Juan Pascual, Scarmeas Nikolaos, Scheltens Philip, Schott Jonathan M, Seripa Davide, Sie Daoud, Sims Rebecca, Sistermans Erik A, Sorbi Sandro, Sleegers Kristel, van Spaendonk Resie, van Swieten John C, Tesi Niccolo', Tijms Betty M, Tsolaki Magda, Uitterlinden André G, Vijverberg Jort, Visser Pieter Jelle, Wagner Michael, Williams Julie, Zarea Aline, EADB Consortium, Génin Emmanuelle, Holstege Henne, Gudbjartsson Daniel F, Wallon David, Lecourtois Magalie, Fernandez Maria Victoria, Stefansson Hreinn, Jacquemont Sébastien, Lambert Jean-Charles, van der Lee Sven J, Charbonnier Camille, Nicolas Gaël

Аннотация

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.

Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk.

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