An Alzheimer’s disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimer’s disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E ( KLC1_vE ), an amyloid-β (Aβ) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for Aβ accumulation confirmed that Klc1_vE drives Aβ pathology. Using omics methods, we revealedthe molecular pathway of a complex disease supported by human and mouse genetics.