Genome‐wide association studies identify novel loci in rapidly progressive Alzheimer's disease
Ping Wang, Audrey Lynn, Kristy Miskimen, Yeunjoo E. Song, Thomas Wısnıewskı, Mark L. Cohen, Brian S. Appleby, Jiri Safar, Jonathan L. Haines
Abstract
Abstract INTRODUCTION Recent data suggest that distinct prion‐like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS Previously known AD risk loci were examined in rpAD cases. Genome‐wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS We identified 115 pathology‐confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non‐Hispanic European ancestry. Compared to the clinical cohort, pathology‐confirmed rpAD had higher frequencies of apolipoprotein E ( APOE ) ε4 and rare missense variants in AD risk genes. A novel genome‐wide significant locus ( P < 5×10 −8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology‐confirmed rpAD ( P < 1×10 −5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.