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

Gene dosage effect: 22q11.21 deletions restricted to early-onset cases and duplications enriched in controls, narrowed to the SCARF2-KLHL22-MED15 region; SCARF2 overexpression increases amyloid-beta uptake.

The role of copy-number variants in non-monogenic Alzheimer disease remained poorly characterized, whereas APP duplications cause autosomal dominant forms. The authors analyzed rare copy-number variants, frequency below 1%, in 22,319 exomes (4,150 early-onset cases aged 65 or younger, 8,519 late-onset cases, 9,650 unaffected controls) with harmonized calling and quality control. Early-onset cases showed an increased burden of rare copy-number variants affecting coding genes, particularly deletions in Alzheimer-related genes, and integrated loss-of-function analysis combining short truncating variants with deletions implicated ABCA1 (OR 5.77 [2.25; 17.06], p = 0.0002) and ABCA7 (OR 2.29 [1.44; 3.65], p = 0.0006), with CTSB appearing as a candidate (OR 5.03 [1.50; 20.71], p = 0.0089). Exome-wide gene-level dosage analysis highlighted 18 genes across five loci at a false discovery rate below 10%, including the 22q11.21 central region where deletions were restricted to early-onset disease, including one de novo event, and duplications were enriched in controls; the locus was narrowed to the SCARF2-KLHL22-MED15 region. Replication in 33,977 affected individuals and 362,322 controls confirmed the association of 22q11.21 dosage with exome-wide significance (OR for SCARF2 0.34 [0.21; 0.53], mega-p = 5.52 × 10⁻⁷), and SCARF2 overexpression increased amyloid-beta uptake.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Copy-number variant calling on exome data remains technically thankless, and the value of this work lies in harmonization across 22,319 exomes followed by replication in more than 390,000 individuals, with a cellular experiment consistent with the direction of effect. The most directly useful information in clinic concerns 22q11.21 deletion carriers, already followed for DiGeorge syndrome: an increased Alzheimer risk, concentrated here on early-onset disease, now belongs in the discussion, even though no absolute risk figure is available. The protective effect of duplications is the most surprising result and the one requiring most caution, exome data not being the ideal substrate for quantifying dosage.

Analysis by Dr Thibaut Benquey