Genome-wide analysis identifies a novel LINC-PINT splice variant associated with vascular amyloid pathology in Alzheimer’s disease

• DOI: 10.1186/s40478-021-01199-2
• Publication Date: 2021-05-21T08:03:04Z
• Authors: Joseph S. Reddy; Mariet Allen; Charlotte C. G. Ho; Stephanie R. Oatman; Özkan İş; Zachary S. Quicksall; Xue Wang; Jiangli Jin; Tulsi A. Patel; Troy P. Carnwath; Thuy T. Nguyen; Kimberly G. Malphrus; Sarah J. Lincoln; Minerva M. Carras...; Julia E. Crook; Takahisa Kanekiyo; Melissa E. Murray; Guojun Bu; Dennis W. Dickson; Nilüfer Ertekin-T...
• Keywords: Neuropathology; Apolipoprotein E; Genome-wide Association Study; Genetic Association

Abstract Cerebral amyloid angiopathy (CAA) contributes to accelerated cognitive decline in Alzheimer’s disease (AD) dementia and is a common finding at autopsy. The APOE ε4 allele male sex have previously been reported associate with increased CAA AD. To inform biomarker therapeutic target discovery, we aimed identify additional genetic risk factors biological pathways involved this vascular component of AD etiology. We present genome-wide association study pathology cases report sex- -stratified assessment phenotype. Genome-wide genotypes were collected from 853 neuropathology-confirmed scored for across five brain regions, imputed the Haplotype Reference Consortium panel. Key variables tested all individuals stratified subsets. Pathway enrichment was run each analyses. Implicated loci further investigated functional consequences using transcriptome data 1,186 samples representing seven regions profiled as part AMP-AD consortium. confirmed sex, neuropathology CAA, identified novel locus, LINC-PINT, associated lower amongst APO Eε4-negative (rs10234094-C, beta = −3.70 [95% CI −0.49—−0.24]; p 1.63E-08). Transcriptome profiling revealed higher LINC-PINT expression levels cases, rs10234094-C altered splicing. analysis indicates variation genes neuronal health function are linked patients. Further studies diverse cohorts needed assess broader translation our findings.