Rare CNV dosage associated with Alzheimer's disease risk in exome case-control study

Copy number variants (CNVs), defined as deletions or duplications of genomic segments >100 bp, are major contributors to human disease, yet their role in non-monogenic Alzheimer disease (AD) remains poorly characterized. We analyzed rare CNVs from 22,319 exomes, including 4,150 early-onset AD (EOAD), 8,519 late-onset AD and 9,650 unaffected controls. EOAD cases showed increased burdens of rare CNVs, particularly rare deletions within AD-related genes. Loss-of-function analyses implicated deletions in ABCA1 and ABCA7 and identified CTSB as a candidate locus. Exome-wide gene-level dosage analysis highlighted 18 genes across five loci, including chr22q11.21, where deletions were restricted to EOAD and duplications enriched in controls. Replication in 33,992 cases and 362,305 controls confirmed AD-risk reduction in 22q11.21 duplication carriers (mega-analysis dosage OR(SCARF2)=0.34, p=5.52x10-7). SCARF2 overexpression increased amyloid-{beta} uptake in vitro, supporting a functional link. These findings highlight CNVs as contributors to AD risk and identify 22q11.21 dosage as a strong genetic determinant. 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: 7 APP and 2 MAPT duplications). 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 different loci with a false discovery rate (FDR) below 10%, including the chr22q11.21 central region (FDR=0.0386), a region in linkage disequilibrium with the APOE locus on chr19 (FDR=0.0271), and two single-gene loci, namely FADS6 (FDR=0.0271), and ADI1 (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 the SCARF2-KLHL22-MED15 region at the 22q11.21 locus. In addition, the integrated LOF analysis highlighted rare deletions in the known AD-risk genes ABCA1 and ABCA7 that represented 10% (3/30) and 8.6% (10/115) of LOF alleles of these genes, respectively, as well as 4 TYROBP deletions. Finally, we identify CTSB LOF alleles as candidate rare AD risk factors (p=0.0089). In conclusion, our results show that carriers of a deletion of FADS6 or a 22q11.21 deletion encompassing the SCARF2-KLHL22-MED15 region, including 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.