A transcriptome association study of AD risk genes in the pathogenesis of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) affects millions of people with no effective treatments making it vital to identify potential therapeutic targets. Genome‐wide association studies (GWAS) have consistently identified AD susceptibility loci or ‘hits’. Few of these are differentially expressed in brain transcriptomic studies, meaning that their effects may be manifest via interacting or downstream transcripts. We have recently used machine learning on human brain transcriptomic data to identify and validate an association between lactoferrin and amyloid (1). Here we apply the same method to identify the transcripts associated with AD susceptibility ‘loci’.MethodAnalyses were performed on the disease‐linked genes from our machine learning analyses (LTF, ADAMTS2, PPDPF, PRTN3) and the combined 58 GWAS risk loci from two recent studies (2, 3). Boruta was used to find transcripts associated with each GWAS ‘hit’ and our genes of interest in two pathologically confirmed AD cohorts (Religious Orders Study and Memory and Aging project, Mount Sinai Brain Bank). The GWAS hits and associated transcripts were correlated with disease markers (cognition, plaque number, Braak score, CERAD score) to find direct and indirect effects.ResultsTREM2 was the GWAS ‘hit’ most correlated with disease markers in both cohorts but most GWAS ‘hits’ were either not correlated or negatively correlated with disease markers. Among the GWAS ‘hit’‐associated transcripts, SWAP70, EMP3, and WWTR1 were positively and VGF negatively correlated with disease markers in both cohorts. For our genes of interest, ADAMTS2 and PPDPF shared overlaps between their associated transcripts and that of GWAS ‘hit’ ABCA7. LTF was linked with TREM2 and associated with plaques in both cohorts.ConclusionThis study has teased apart nascent associations between known susceptibility genes and gene expression data from the AD brain, but it also hints that consideration of pathological sub‐phenotypes are required to make greater progress in understanding AD pathogenesis.1. Tsatsanis et al. The acute phase protein lactoferrin is a key feature of AD …. Mol Psychiatry. 2021;26(10):5516‐31.2. Yang et al. A human brain vascular atlas reveals diverse cell mediators of AD risk. BioRxiv [Preprint]. 2021.3. Wightman et al. A GWAS with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276‐82.