Extremely rare CNVs contributing to Alzheimer disease risk: a case-control association analysis of exome sequencing data from 22,319 individuals
Authors: Quenez Olivier , Schramm Catherine , Cassinari Kévin , Nicolas Aude , Groeneveld Joan , Huguet Guillaume , Grenier-Boley Benjamin , Hulsman Marc , Richard Anne-Claire , Rousseau Stéphane , Ahmad Shahzad , Amin Najaf , Amouyel Philippe , Belbin Olivia , Bellenguez Céline , Berr Claudine , Boland Anne , 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. , Fernandez Victoria , van der Flier Wiesje M. , Fortea Juan , Fox Nick C. , Frikke-Schmidt Ruth , Galimberti Daniela , Genin Emmanuelle , Ghidoni Roberta , Giedraitis Vilmantas , Gille Johan J. P. , Grozeva Detelina , Guerreiro Rita , Grünblatt Edna , Hardy John , Riedel-Heller Steffi G. , Hiltunen Mikko , Holmes Clive , Holstege Henne , 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. , 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 , Uitterlinden André G. , Tsolaki Magda , Visser Pieter Jelle , Wagner Michael , Williams Julie , Zarea Aline ,   EADB Consortium, Wallon David , Jacquemont Sébastien , Lambert Jean-Charles , van der Lee Sven J. , Charbonnier Camille , Nicolas Gaël 
Published: November 2024

Rare coding single nucleotide variants (SNV) and short insertions or deletions (indels) contribute to Alzheimer disease (AD) genetic risk, from pathogenic variants in autosomal dominant genes to risk factors with diverse effects. In contrast, copy number variants (CNV) have been scarcely studied, with the exception of a few autosomal dominant examples, such asAPPgene duplications.

We took advantage from a large case-control dataset of 22,319 exomes (4,150 early-onset AD (EOAD, onset ≤65 years), 8,519 late onset AD (LOAD) and 9,650 controls) to detect CNVs. We first identified 17 causative CNVs in autosomal dominant genes (9 novel: 7APPand 2MAPTduplications). After exclusion of carriers of these, we performed an original two-step analysis: (i) a protein-coding genome-wide analysis at the transcript level using a gene dosage strategy (EOAD versus controls) and then (ii) an integrated loss-of-function (LOF) analysis gathering short truncating variants with CNV-deletions in genes prioritized in (i) and in a list of known AD risk genes.

We identified AD association with dosage of 20 genes at 4 differentlociwith a false discovery rate (FDR) below 10%, including the chr22q11.21 central region (FDR=0.0386), a region in linkage disequilibrium with theAPOElocus on chr19 (FDR=0.0271), and two single-gene loci, namelyFADS6(FDR=0.0271), andADI1(FDR=0.0916). Replication in an independent dataset made of genotyping array data from 2,780 EOAD cases, 15,222 LOAD cases and 273,979 controls was consistent with the results obtained in the discovery dataset. The integrated LOF analysis helped narrowing the region of interest to theSCARF2-KLHL22-MED15region at the 22q11.21 locus. In addition, the integrated LOF analysis highlighted rare deletions in the known AD-risk genesABCA1andABCA7that represented 10% (3/30) and 8.6% (10/115) of LOF alleles of these genes, respectively, as well as 4TYROBPdeletions. Finally, we identifyCTSBLOF alleles as candidate rare AD risk factors (p=0.0089).

In conclusion, our results show that carriers of a deletion ofFADS6or a 22q11.21 deletion encompassing theSCARF2-KLHL22-MED15region, including some patients with DiGeorge syndrome, may have a higher risk of developing AD. CNVs represent a source of genomic variation that can contribute to AD etiology in new genes but also in GWAS defined-genes.