Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease

Abstract

ABSTRACTINTRODUCTIONThe APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus have not been fully characterized.METHODSTo identify novel AD-linked functional elements within theAPOElocus, we integrated SNP variants with RNA-seq, DNA methylation, and ChIP-seq data from human postmortem brains.RESULTSWe identified an AD-linkedAPOEtranscript (jxn1.2.2) observed in the dorsolateral prefrontal cortex (DLPFC). TheAPOEjxn1.2.2 transcript is associated with brain neuropathological features in DLPFC. We prioritized an independent functional SNP, rs157580, significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. rs157580 is located within active chromatin regions and predicted to affect brain-related transcriptional factors binding affinity. rs157580 shared the effects on the jxn1.2.2 transcript between European and African ethnic groups.DISCUSSIONThe novelAPOEfunctional elements provide potential therapeutic targets with mechanistic insight into the disease’s etiology.