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

INTRODUCTION The 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. METHODS To 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. RESULTS We 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. DISCUSSION The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease’s etiology. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The ROSMAP was supported by the National Institute on Aging (NIA) RF1AG57473, P30AG010161, R01AG015819, R01AG017917, U01AG46152, U01AG61356, RF1AG059082, P30AG072975, and R01AG036042. The authors would like to acknowledge NIA P30AG066546, U01 AG058589, R01 AG061872, U01 AG052409, R01 AG059421. The authors also acknowledge Bill and Rebecca Reed Endowment for Precision and Palliative Medicine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript