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

Abstract

INTRODUCTIONThe APOE gene is the strongest genetic risk factor for late-onset Alzheimers Disease (LOAD). However, the gene regulatory mechanisms at this locus have not been fully characterized. METHODSTo identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with RNA-seq, DNA methylation, and ChIP-seq data from human postmortem brains. RESULTSWe identified an AD-linked APOE transcript (jxn1.2.2) observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 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 novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the diseases etiology.