Exome analysis of 22,319 individuals links extremely rare CNVs and 22q11.21 dosage to Alzheimer's risk

Abstract

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.