Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk
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 (OR SCARF2 = 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.
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BibTeX
@article{quenez2026exome,
title = {{Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk}},
author = {Olivier Quenez and Catherine Schramm and Kévin Cassinari and Aude Nicolas and Joan Groeneveld and Guillaume Huguet and Benjamin Grenier-Boley and Marc Hulsman and G. Bragi Walters and Itziar de Rojas and Anne Rovelet-Lecrux and Sébastien Feuillette and Laetitia Miguel and Anne-Claire Richard and Stéphane Rousseau and Shahzad Ahmad and Najaf Amin and Philippe Amouyel and Olivia Belbin and Céline Bellenguez and Claudine Berr and Paola Bossù and Femke Bouwman and Jose Bras and Jordi Clarimon and Antonio Daniele and Jean-François Dartigues and Stéphanie Debette and Jean-François Deleuze and Nicola Denning and Oriol Dols-Icardo and Cornelia van Duijn and Juan Fortea and Nick Fox and Ruth Frikke-Schmidt and Daniela Galimberti and Roberta Ghidoni and Vilmantas Giedraitis and Johan J.P. Gille and Detelina Grozeva and Rita Guerreiro and Edna Grünblatt and John Hardy and Steffi Riedel-Heller and Mikko Hiltunen and Clive Holmes and Jakub Hort and Holger Hummerich and M. Arfan Ikram and M. Kamran Ikram and Martin Ingelsson and Iris Jansen and Amit Kawalia and Robert Kraaij and Patrick Kehoe and Marc Lathrop and Morgane Lacour and Afina Lemstra and Alberto Lleó and Lauren Luckcuck},
journal = {American Journal of Human Genetics},
year = {2026},
month = oct,
doi = {10.1016/j.ajhg.2026.07.013},
url = {https://hal.science/hal-05842705v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exome analysis of 22,319 individuals links extremely rare copy-number variants and 22q11.21 dosage to Alzheimer risk
AU - Olivier Quenez
AU - Catherine Schramm
AU - Kévin Cassinari
AU - Aude Nicolas
AU - Joan Groeneveld
AU - Guillaume Huguet
AU - Benjamin Grenier-Boley
AU - Marc Hulsman
AU - G. Bragi Walters
AU - Itziar de Rojas
AU - Anne Rovelet-Lecrux
AU - Sébastien Feuillette
AU - Laetitia Miguel
AU - Anne-Claire Richard
AU - Stéphane Rousseau
AU - Shahzad Ahmad
AU - Najaf Amin
AU - Philippe Amouyel
AU - Olivia Belbin
AU - Céline Bellenguez
AU - Claudine Berr
AU - Paola Bossù
AU - Femke Bouwman
AU - Jose Bras
AU - Jordi Clarimon
AU - Antonio Daniele
AU - Jean-François Dartigues
AU - Stéphanie Debette
AU - Jean-François Deleuze
AU - Nicola Denning
AU - Oriol Dols-Icardo
AU - Cornelia van Duijn
AU - Juan Fortea
AU - Nick Fox
AU - Ruth Frikke-Schmidt
AU - Daniela Galimberti
AU - Roberta Ghidoni
AU - Vilmantas Giedraitis
AU - Johan J.P. Gille
AU - Detelina Grozeva
AU - Rita Guerreiro
AU - Edna Grünblatt
AU - John Hardy
AU - Steffi Riedel-Heller
AU - Mikko Hiltunen
AU - Clive Holmes
AU - Jakub Hort
AU - Holger Hummerich
AU - M. Arfan Ikram
AU - M. Kamran Ikram
AU - Martin Ingelsson
AU - Iris Jansen
AU - Amit Kawalia
AU - Robert Kraaij
AU - Patrick Kehoe
AU - Marc Lathrop
AU - Morgane Lacour
AU - Afina Lemstra
AU - Alberto Lleó
AU - Lauren Luckcuck
PY - 2026
DA - 2026/10/28
JO - American Journal of Human Genetics
DO - 10.1016/j.ajhg.2026.07.013
UR - https://hal.science/hal-05842705v1
AB - 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 (OR SCARF2 = 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.
SN - 0002-9297
SN - 1537-6605
ER -